Biological Components of Substance Abuse and Addictionbiological components of substance abuse and addiction. Two biological factors contribute to substance abuse and addiction: the

Biological Components of Substance Abuseand Addiction

September 1993

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Recommended Citation:U.S. Congress, Mice of Technology Assessment, BioZogicaZ Components ofSubstance Abuse and Addiction, OTA-BP-BBS-1 17 (Washington, DC: U.S.Government printing Offke, September 1993).

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sForeword

ubstance abuse and addiction are complex phenomena that defy simpleexplanation or description. A tangled interaction of factors contributes toan individual’s experimentation with, use, and perhaps subsequent abuseof drugs. Regardless of the mix of contributing factors, the actions and

effects exerted by drugs of abuse underlie all substance abuse and addiction. Inorder to understand substance abuse and addiction it is first necessary tounderstand how drugs work in the brain, why certain drugs have the potentialfor being abused, and what, if any, biological differences exist amongindividuals in their susceptibility to abuse drugs.

This background paper is the first of two documents being produced byOTA as part of an assessment of Technologies for Understanding the RootCauses of Substance Abuse and Addiction. The assessment was requested by theHouse Committee on Government Operations, the Senate Committee onGovernmental Affairs, and the Senate Committee on Labor and HumanResources. This background paper describes biological contributing factors tosubstance abuse and addiction. The second document being produced by thisstudy will discuss the complex interactions of biochemical, physiological,psychological, and sociological factors leading to substance abuse andaddiction.

OTA gratefully acknowledges the generous help of the Advisory Panel,contributors, and reviewers who gave their time to this project. OTA, however,remains solely responsible for the contents of this background paper.

a “ + - -Roger C. Herdman, Director

iii

Advisory PanelPatricia EvansChairBayview-Hunter’s PointFoundationSan Francisco, CA

Marilyn Agulrre-MollnaRobert Wood Johnson Medical

SchoolPiscataway, NJ

Jeffrey G. BeckerThe Beer InstituteWashington, DC

Lawrence S. Brown, Jr.Addiction Research and

Treatment Corp.Brooklyn, NY

Mary EdwardsCamden HouseDetroit, Ml

Bernard Ellis, Jr.New Mexico Department of

HealthSanta Fe, NM

Robbie M. JackmanState of TennesseeDepartment of Public HealthNashville, TN

Sheppard KellamSchool of Hygiene and

Public HealthThe Johns Hopkins UniversityBaltimore, MD

Herbert KleberCollege of Physicians and

surgeonsColumbia UniversityNew York NY

George KoobDepartment of NeuropharmacologyThe Scripps Research InstituteLa Jolla, CA

Mary Jeanne KreekDepartment of Biology and

Addictive DiseasesThe Rockefeller UniversityNew York, NY

John LucasJohn Lucas EnterprisesHouston, TX

Spero MansonUniversity Health Science CenterColorado Psychiatric HospitalDenver, CO

Roger Meyer

David F. MustoChild Studies CenterYale UniversityNew Haven, CT

Ruben OrtegaRuben Ortega AssociatesPhoenix, AZ

Sue RuscheNational Families in ActionAtlanta, GA

Lawrence WallackSchool of Public HealthUniversity of California BerkeleyBerkeley, CA

Kenneth E. WarnerSchool of Public HealthUniversity of MichiganAnn Arbor, MI

Roger W. WilkinsRobinson Professor of History and

American CultureGeorge Mason UniversityFairfax, VA

Department of PsychiatryUniversity of ConnecticutFarmington, CT

NOTE: OTA apprecutes and is grateful for the valuable assistance and thoughtful critiques provided by the advisory panel members. The paneldoes not, however, necessarily approve, “disapprove, or endorse this report. OTA assumes full responsibility for the report and the accuracy of itscontents.

iv

Clyde BehneyAssistant DirectorHealth, Life Sciences

and the Environment

Michael GoughProgram ManagerBiological and Behavioral Sciences

Program

PRIMARY CONTRACTOR

David R. LiskowskyArlington, VA

Kevin W. O’ConnorProject Director

Jennifer SchmidtAnalyst

Thomas R. VischiOTA Fellow

Ellen McDermottResearch Assistant

CONTRACTORS

Carter BlakeyEditorBethesda, MD

Preject Staff

Theodore J. CiceroWashington University School of

Medicine

Stephen DinwiddieWashington University School of

Medicine

William J. McBrideIndianaUniversity School of

Medicine

ADMINISTRATIVE STAFF

Cecile ParkerOffice Administrator

Linda Rayford-JourniettePC! Specialist

Jene LewisAdministrative Secretary

Theodore ReichWashington University School of

Medicine

contents

1

2

3

4

Executive Summary 1Drug Action 2Genetic Factors 6Role of Learining 7

Basic Concepts 9The Brain Reward System 10Neuroadaptive Responses 11Abuse Liability 13Role of Learning 15Chapter 2 References 16

The Neuropharmacology of Drugs of Abuse 19Neurophannacology 20Drugs of Abuse 21

summary 35Chapter 3 References 36

Genetics 39Do Inherited Factors Exist? 40What Is Inherited? 43

Summary 50Chapter 4 References 51

APPENDIXES

A The Drug Evacuation Committee of the College onProblems of Drug Dependence 59

B Acknowledgments 61

VI

s ubstance abuse and addiction are complex phenomenathat defy simple explanation or description. A tangledinteraction of factors contributes to an individual’sseeking out, using, and perhaps subsequently abusing

drugs. Since more individuals experiment with drugs thaneventually develop substance abuse problems, great interestpersists in understanding what differentiates these groups.Factors that can play a role in drug abuse susceptibility includea person psychological makeup (e.g., self-esteem, propensity totake risks, irnpulsivity, depression), biological response to drugsand environmental situation (e.g., peer groups, family organiza-tion, socioeconomic status), and the availability of drugs. Theexact combination of elements that leads to substance abuse andaddiction varies among individuals.

Regardless of the mix of contributing factors, the actions andeffects that drugs of abuse exert underlie all substance abuse andaddiction. In order to understand substance abuse and addictionone must first understand how drugs work in the brain, whycertain drugs have the potential for abuse, and what, if any,biological differences exist among individuals in their suscepti-bility to abuse drugs. While numerous factors ultimatelycontribute to an individual’s drug-taking behavior, understand-ing the biological components is crucial to a better comprehen-sion of substance abuse and addiction. In this background paper,the Office of Technology Assessment (OTA) describes thebiological components of substance abuse and addiction.

Two biological factors contribute to substance abuse andaddiction: the effects drugs of abuse exert on the individual, andthe biological status of the individual taking drugs. The former

ExecutiveSummary 1

w

1

2 I Biological Components of Substance Abuse and Addiction

Box l-A–NeuropharmacologyNeurons are the cells that process information in the brain. Neurotransmitters are chemicals released by

neurons to communicate with other neurons. When a neuron is activated it releases a neurotransmitter into thesynapse, the gap between two neurons (figure l-l). The molecules of the neurotransmitter move across thesynapse and attach, or bind, to proteins called receptors in the outer membrane of an adjacent ceil. Once aneurotransmitter activates a receptor, it unbinds from the receptor and is removed from the synapse. This is doneeither by the neurotransmitter being taken backup into the neuron that released it or by its being chemically brokendown.

For each neurotransmitter in the brain, there are several specific receptors to which it can attach. Binding bythe neurotransmitter activates the receptor. Receptors can be linked to a variety of membrane and cellularmechanisms that are turned on or off by the activation of the receptor. while receptors are specific for aneurotransmitter, there maybe a variety of receptor subtypes, linked to different cellular mechanisms and todifferent neuronal circuits, that all respond to the same neurotransmitter. In this way one neurotransmitter can havediverse effects indifferent areas of the brain. Many chemicals have been identified as neurotransmitters. Soresare of particular relevance to the rewarding properties of drugs of abuse. These include dopamine, norepinephrine,serotonin, opioids and other neuropeptides, gamma amino butyric add (GABA), and glutamate.

A neuron can have thousands of receptors for many different neurotransmitters. Some neurotransmittersactivate neurons (excitatory neurotransmitters), while others decrease neuron activity (inhibitory neurotransmit-ters). Sometimes a receptor for one neurotransmitter can affect a receptor for another neurotransmitter. In suchcases, the receptors are biochemically coupled: the activation of one modulates the function of the other, eitherincreasing or decreasing its activity. A neuron can also have receptors for the neurotransmitter it releases. Suchreceptors are acted on by the neuron’s own neurotransmitter to regulate the release of the neurotransmitter. Thus,these so-called autoreceptors act as a feedback mechanism to regulate a neuron’s activity. The activity ofa neuronwill be determined by the cumulative activity of all of its various receptors.

Drugs that work in the brain, including drugs of abuse, alter normal neuropharmacological activity througha varietyofdifferent mechanisms. They can affect the production, release, or reuptake of a neurotransmitter, theycan mimic or block the action of a neurotransmitter at a receptor, or they can interfere with or enhance the activityof a membrane or cellular mechanism associated with a receptor. Prolonged drug use has the potential to altereach of these processes.SOURCE: office of Technology Assessment, 1993.

relates to the acute mechanisms of action of drugs drugs is that most of these drugs act, at least inof abuse in the brain and the long-term effects thatoccur after chronic exposure. The latter pertainsto an individual’s biological constitution, mostimportantly the presence of inherited characteris-tics, which affects that person’s response to adrug.

DRUG ACTION

I Acute ActionsDrugs of abuse alter the brain’s normal balance

and level of biochemical activity (box l-A). Whatseparates drugs of abuse from other psychoactive

part, on those areas of the brain that mediatefeelings of pleasure and reward (box l-B).

The ability to induce activity in the so-calledbrain reward systems gives drugs of abuse posi-tive reinforcing actions that provoke and supporttheir continued use and abuse. Reinforcement isdefined as the likelihood that the consequences oftaking the drug will increase the behavior directedtoward seeking that drug. Put more simply,individuals who use drugs experience someeffect, such as pleasure, detachment, or relieffrom distress, that initially establishes and thenmaintains drug self-administration. The con-

Chapter l—Executive Summary | 3

Figure l-l—The Synapse andAssociated Structures

T T

Neurotransmitters ReceptorsReceiving cell

SOURCE: Office of Technology Assessment, 1993.

sequence of taking the drug enhances the prospectthat it will continue to be used for some real orperceived effect and eventually compulsive self-administration. In fact, the capacity of a drug tosupport self-administration in experimental ani-mals is a measure of the drug’s strength as areinforcer.

While growing evidence indicates that thebrain reward system likely plays a role in thereinforcing properties of most drugs of abuse, theprecise mechanisms involved in all drugs of abusehave yet to be completely described. The reward-ing properties of stimulant drugs such as cocaineand amphetamines are due to a direct increase inthe activity of the neurotransmitter dopamine inthe mesocorticolimbic dopamine pathway (seebox l-B). Opiates, on the other hand, indirectlystimulate dopamine activity by activating otherneurotransmitter pathways, which in turn increasedop amine activity in the mesocorticolimbic path-way (MCLP). Similarly, alcohol, barbiturates,and benzodiazepines also indirectly activate MCLP.

All of these drugs have strong reinforcing proper-ties. Phencyclidine (PCP) is also a strong rein-forcer but its relationship, if any, to activity inMCLP has not been established. Other drugs areeither weak reinforcers or have not been shown tosupport self-administration in animal experi-ments. Nicotine activates dopamine neurons inthe mesocorticolimbic system. However, whencompared with cocaine or amphetamine, t h i s effect is modest. Likewise, caffeine is a weakreinforcer, but the precise mechanisms of itsreinforcement are unclear. Finally, while canna-bis and lysergic acid diethylamide (LSD) producepositive effects that clearly support their use,there is currently little empirical evidence thatthey act as reinforcers in controlled experiments.

# Chronic ActionsChanges occur in the brain when it is exposed

to drugs. Beyond their immediate, rewardingproperties, drugs of abuse, when used on achronic, long-term basis, can cause either perma-nent changes in the brain or alterations that maytake hours, days, months, even years to reverse ondrug cessation. These changes are adaptive re-sponses related to the pharmacological action ofa given drug that occur in the brain to counter theimmediate effects of a drug.

Tolerance develops to a drug when, followinga prolonged period of use, more of the drug isrequired to produce a given effect. Toleranceoccurs with many types of drugs and is a common,but not necessary, characteristic of drugs ofabuse. Tolerance can contribute to drug-takingbehavior by requiring that an individual takeprogressively larger doses of a drug to achieve adesired effect.

Dependence occurs when, with prolonged useof a drug, neurons in the brain adapt to the drug’spresence such that the use of the drug is nowrequired to maintain normal function in the cells.On abrupt withdrawal of the drug, the neuronbehaves abnormally and a “withdrawal syn-drome” ensues, Generally, the withdrawal syn-


1 An~~a@~i~ ofoelislnthe brafnthat share thesarneanatomlcal ~a~ ~~~-; *Sarrm funotlon.SOURC~Q.F. Korb, ‘DrugaofAbuoa:Anabmy, Phannaodogy, and FunotbnofRcward Pathwayq” ~bh~~l&177-lS4, 19DZ G.F. Koob, “thud Mdanlam d Drug Rdnfo romtnt” P.W. Kal!w, ad H.H. Satwun (ocIB.), 7kikudddw dLMl#afldAkoholAdotfm AnmhofthoAm?ican Aca&ny of Sdanoss S54:171-191, 1992.

drome is characterized by a series of signs andsymptoms that are opposite to those of the acuteeffects of the drug. Withdrawal creates a cravingor desire for the drug and plays a very strong rolein recurrent patterns of relapse, in maintainingdrug-seeking behavior to forestall the withdrawalsyndrome, and in the need to reestablish somesense of normalcy.

Sensitization occurs when the effects of a givendose of a drug increase after repeated administra-tion. Thus, sensitization is the opposite of toler-ance. Sensitization to a drug’s behavioral effectscould play a significant role in supporting drug-taking behavior.

For example, while tolerance to some of theeffects of cocaine and amphetamines develops,sensitization to other of their effects can alsooccur. Also, while it is unclear horn available datawhether tolerance develops to cocaine’s reinforc-ing effects, the notion is supported by someexperimental evidence and anecdotal reports

born cocaine users that the drug’s euphoricactions diminish with repeated use. Tolerancealso develops to the effects, including the rein-forcing properties, of opiates and alcohol.

A withdrawal syndrome of varying severity isassociated with most drugs of abuse. Barbiturates,alcohol, stimulants, opiates, and benzodiazepinesproduce pronounced and sometimes severe with-drawal symptoms, while those for nicotine andcaffeine are less intense. A mild withdrawal isassociated with cannabis use, while there is noevidence of a withdrawal syndrome related toLSD.

I Abuse LiabilityThe abuse liability of a drug is a measure of the

likelihood that its use will result in drug addic-tion. Many factors ultimately play a role in anindividual’s drug-taking behavior; nevertheless,the abuse potential of a drug is related to itsintrinsic rewarding properties and/or the neu-

Chapter l–Executive Summary | 5

roadaptive responses that result from its pro-longed use. Drugs can be tested and screened fortheir abuse liability using animals as models. Thecriteria that can be evaluated to classify a drug ashaving significant abuse potential are pharmacol-ogical equivalence to known drugs of abuse,demonstration of reinforcing effects, tolerance,and physical dependence. The capacity to pro-duce reinforcing effects is essential to any drugwith significant abuse potential, whereas toler-ance and physical dependence most commonlyoccur but are not absolutely required to make sucha determination.

SELF-ADMINISTRATIONThe predominant feature of all drugs with

significant abuse potential properties is that theyare self-administered. In fact, self-administrationof a drug to the point when the behavior becomesobsessive and detrimental to the individual is theprimary criterion that must be met to classify adrug as having significant potential for addiction.In addition to self-administration, another con-tributing factor to abuse liability is the notion ofcraving and the tendency of individuals to relapseto drug use during withdrawal. Although cravingis a difficult term to quantify, once a drug isvoluntarily or involuntarily withdrawn, the desireto take the drug can play a role in the relapse tosubstance abuse.

Animals can be readily trained to self-administer drugs. Animal models of self-administration provide a powerful tool that cangive a good indication of the abuse liability ofnew or unknown drugs. These models also permitan examination of the behavioral, physiological,and biological factors that lead to sustainedself-administration.

DRUG DISCRIMINATIONAnother tool in the assessment of abuse liabil-

ity of drugs is drug discrimination, which refers tothe perception of the effects of drugs. Specifi-cally, animals or humans trained to discriminate

Figure 1-2—The Mesocortlcolimbic Pathway

Ventral\tegmental varea

The mesocorticolimbic pathway from the ventral tegmentalarea to the nucleus accumbens and the frontal cortex is a keycomponent of the brain reward system for drug reinforcement.SOURCE: Office of Technology Assessment , 1 9 9 3 .

a drug from a placebo show a remarkable abilityto distinguish that drug from other drugs withdifferent properties. These procedures also permita determination of whether the subject considersthe drug to be the pharmacological equivalent ofanother drug. Pharmacological equivalence refersto the fact that drugs of a particular class, such asopiates, stimulants, and depressants, cause aseries of effects on the brain and other organs thatcollectively constitute their pharmacological pro-file.

DEPENDENCE AND TOLERANCEDependence and tolerance can readily be

induced in animals by chronic administration ofdrugs. Following abrupt withholding of a drug, awithdrawal syndrome will often develop and themotivation for self-administration of the drugmay be increased. Thus, the capacity of a drug toinduce neuroadaptive motivational changes canbe assessed. Furthermore, since the understand-ing of the neuroadaptive changes that take placeduring the development of physical dependenceand tolerance are poorly understood in humans,animal models offer a unique opportunity to carryout experiments designed to address these issues.

6 | Biological Components of Substance Abuse and Addiction

GENETIC FACTORSProgress in understanding the genetics of

various conditions and diseases has brought withit a realization that substance abuse and addictionprobably involve a genetic component. That is,hereditary biological differences make some indi-viduals either more or less susceptible to drugdependency than others. While it seems likelythat inherited differences exist, a genetic compo-nent alone is insufficient to produce substanceabuse and addiction.

Unlike disorders, such as Huntington’s diseaseand cystic fibrosis, that result from the presenceof alternations in a single gene, a genetic compo-nent of substance abuse is likely to involvemultiple genes that control various aspects of thebiological response to drugs or physiologicalpredisposition to become an abuser. In addition,the complex nature of drug dependency, involv-ing many behavioral and environmental factors,indicates that any genetic component acts inconsort with other nongenetic risk factors tocontribute to the development of substance abuseand addiction. Thus, the presence of a geneticfactor does not ensure drug addiction nor does itsabsence guarantee protection from drug addic-tion.

Two questions arise when considering a ge-netic component to substance abuse and addic-tion: Do inherited factors exist? And, if so, whatare they? To date, much of the work done in thisfield relates to alcoholism. Less is known aboutthe genetic aspects of the abuse of other drugs.

I Do Inherited Factors Exist?Results from family studies, twin studies, and

adoption studies as well as extensive research onanimal models indicate that heredity influencesnormal as well as pathological use of alcohol.Animal studies have established that geneticfactors contribute to alcohol preference, thereinforcing actions of alcohol, alcohol tolerance,and alcohol physical dependence. While fewstudies have examined the genetic component of

vulnerability to the addictive properties of otherdrugs of abuse, evidence from animal studiesconfirms the role of a genetic influence on the useand abuse of drugs other than alcohol. The studyof nonalcoholic drug abuse in humans has beendifficult due to substantially lower populationprevalence and differences in availability and,hence, exposure to these agents. Investigation inthis area is further hampered by the complexity ofsubjects’ drug use: most drug abusers have usedmultiple agents. This has led researchers either toconcentrate on one class of drug or to treat allillicit drug use as equivalent. The tendency tolump all illicit drugs into one category makesresults difficult to interpret or compare.

I What Is Inherited?While study results support the role of a genetic

component in alcoholism and probably other drugabuse, they provide no information about whatexactly is inherited. For example, do individualswith a family history of drug abuse have anincreased susceptibility or sensitivity to the ef-fects of drugs with reinforcing properties? If asusceptibility exists, what are its underlyingbiological mechanisms? Information about inher-ited biological mechanisms is most easily derivedfrom studies of animals bred to have differingresponses to various drugs. However, in humans,few studies have examined the relationship be-tween inherited behavioral traits and the inheritedbiological mechanisms that might underlie them.

In the case of alcohol, studies suggest that lowdoses of alcohol are more stimulating and pro-duce a stronger positive reward in rats bred tohave a high preference for alcohol as comparedwith normal rats. Experimental data indicate thatthis may be due to inherited differences in themesocorticolimbic dopamine system (see boxl-B) and an inherited increased response of thissystem when exposed to alcohol. Also, alcohol-preferring rats have been found to have differentlevels of activity in other neurotransmitter sys-tems that modulate activity in the mesocorti-

Chapter l–Executive Summary | 7

colimbic system. In humans, studies of college-aged individuals indicate that low initial sensitiv-ity to alcohol may be a predictor for alcoholismlater in life.

Studies using the technique of genetic linkageanalysis 1 have attempted to identify genes thatmight be associated with alcoholism in humans.However, the findings of these studies are incon-clusive. While some studies have reported a linkbetween alcoholism and a gene that regulates thenumber of a type of dopamine receptor in thebrain, others have not. The reason for thisdiscrepancy is unclear, but one study has found arelationship between the presence of the gene notonly in alcoholism, but also in other disorderssuch as autism, attention deficit hyperactivitydisorder, and Tourette’s syndrome. Thus, thepresence of the gene may cause an alteration inthe brain dopamine system that somehow exacer-bates or contributes to alcohol abuse, but is notuniquely specific for alcoholism.

Fewer studies have focused on possible inher-ited biological mechanisms associated with theabuse of other drugs. For example, strains of ratsand mice that differ in their sensitivity to thereinforcing effects of cocaine and in their cocaine-seeking behavior have also been observed to havedifferences in the number of dopamine-contain-ing neurons and receptors in certain brain areas.Also, a comparison of one strain of rat thatself-administers drugs of abuse at higher ratesthan another strain found that the higher self-administering strain exhibited differences in theintracellular mechanisms that control activity insome of the neurons in the brain reward system ascompared with the low self-administering strain.Additional studies exploring the role of genes indrug response are needed to more fully under-stand the full range of biological factors associ-ated with drug abuse. The recent development ofnew and more sensitive techniques to analyze

brain activity and processes will facilitate thesestudies.

ROLE OF LEARNINGThe learning that occurs when an individual

takes drugs is an important contributing force inthe continued use and craving of drugs. Drugs ofabuse produce positive or pleasurable feelings inthe user and have reinforcing properties. Inaddition to these effects, drugs of abuse producechanges in numerous organ systems such as thecardiovascular, digestive, and endocrine systems.Both the behavioral and physiological effects ofa drug occur in the context of an individual’sdrug-seeking and drug-using environment. As aresult, environmental cues are present before andduring an individual’s drug use that are consist-ently associated with a drug’s behavioral andphysiological effects. With repetition the cuesbecome conditioned stimuli, that on presentation,even in the absence of the drug, evoke automaticchanges in organ systems and behavioral sensa-tions that the individual experiences as drugcraving. These associations are difficult to re-verse. In theory, repeated presentation of theenvironmental cues, absent the drug, shouldextinguish the conditioned association. Animalstudies indicate that extinction is difficult toachieve and does not erase the original learning,As a result, even once established, the extinctionis readily reversed.

Also, it has long been known that conditioningoccurs in relation to the withdrawal effects ofdrugs. This phenomenon, termed conditionedwithdrawal, results from environmental stimuliacquiring the ability, through classical condition-ing, to elicit signs and symptoms of pharmacolog-ical withdrawal. The emergence of withdrawalsymptoms as a result of exposure to conditionedcues can contribute to drug use relapse by

1 Genetic linkage studies establish an association between an area of a specific chromosome and the expression of a trait. Linkage analysisuses spec~Ic markers that identify the area on a chromosome that might contain the gene of interest. If the marker consistently occurs inassociation with the expressed trai~ then it is likely that the gene of interest is in that chromosomal region.


motivating an individual to seek out and usedrugs.

Thus, exposure to environmental cues associ-ated with drug use in the past can act as a primingforce to motivate voluntary drug-seeking behav-ior. Drug conditioning can help explain the factthat many drug abusers often return to environ-ments associated with drug use, even after beingcounseled not to. The effects of the environmentalstimuli can be similar to the priming effects of alow dose of the drug or result in withdrawalsymptoms. In either case these stimuli can occa-

sion further drug use even after successful detoxi-fication.

The complexity of human responses to drugs ofabuse, coupled with the number of drugs that areabused, complicates understanding of the role ofbiology in drug use and abuse. Nevertheless,scientists know the site of action of many drugs inthe brain, and sophisticated new devices areexpected to improve that understanding. A ge-netic component to drug use and abuse is likely,but it has not been fully characterized.

s imilar to other psychoactive drugs, drugs of abuse alter thebrain’s normal balance and level of biochemical activity.This can include mimicking the action of naturallyoccurring neurotransmitters (chemicals in the brain that

send messages from one nerve cell to another), blockingneurotransmitter action, or in other ways altering the normalchemical actions that mediate the transmission of informationwithin the brain. The ultimate effect is to either elevate or depressactivity in different brain regions (see ch. 3).

What separates drugs of abuse from other psychoactive drugsis that these drugs act, at least in part, on those areas of the brainthat mediate feelings of pleasure and reward. Inducing activity inthe so-called brain reward system gives drugs of abuse positivereinforcing actions that provoke and support their continued useand abuse.

Beyond their immediate, rewarding properties, drugs used ona chronic, long-term basis can cause either permanent changes inthe brain or alterations that may take hours, days, months, evenyears, to reverse on drug cessation. These changes are adaptiveresponses that occur in the brain to counter the immediate effectsof a drug. When drug taking is stopped, these changes are oftenmanifested as effects that are opposite to the initial pleasurabledrug response. The continued administration of drugs to avoidthe aversive effects of drug cessation also contributes to anindividual’s addiction to a drug.

Their immediate and long-term effects imbue drugs of abusewith reinforcing properties. Reinforcement is defined as the

BasicConcepts 2

likelihood that the consequences of taking the drug will increase Ithe behavior directed toward seeking that drug (6). Put more I


simply, individuals who use drugs experiencesome effect, such as pleasure, detachment, orrelief from distress, that initially establishes andthen maintains drug use. Thus, the consequenceof taking the drug enhances the prospect that itwill continue to be used for some real or perceivedeffect and also establishes a need state, hence,engendering compulsive self-administration.

In addition to their reinforcing effects, drugs ofabuse can have a variety of pharmacologicalactions in other areas of the brain and the body.The ultimate effect of a drug will also be shapedby other factors including the dose of the drug, theroute of administration, the physiological statusof the user, and the environmental context inwhich the drug is taken. The subjective experi-ence of the drug user and his or her overt behavioris the result of a combination of these factors andthe drug’s pharmacological action.

THE BRAIN REWARD SYSTEMEating, drinking,g, s e x u a l , a n d m a t e r n a l b e h a v -

iors are activities essential for the survival of theindividual and the species. Natural selection, inorder to ensure that these behaviors occur, hasimbued them with powerful rewarding properties.The brain reward system evolved to process thesenatural reinforcers.

Studies have shown that direct stimulation ofthe areas of the brain involved in the rewardsystem, in the absence of any goal-seeking be-havior, produces extreme pleasure that has strongreinforcing properties in its own right (17). Suchstimulation activates neural pathways that carrynatural rewarding stimuli. Animals with elec-trodes implanted in these areas in such a way thatelectrical impulses produce a pleasurable sensa-tion will repeatedly press a bar, or do any otherrequired task, to receive electrical stimulation.The fact that animals will forego food and drinkto the point of death or will willingly experiencea painful stimulus to receive electrical stimulationof the reward system attests to the powerfulreinforcing characteristics of the reward system.

Most drugs ofrectly, affect the

abuse, either directly or indi-brain reward system. This is

evident by the fact that administration of mostdrugs of abuse reduces the amount of electricalstimulation needed to produce self-stimulationresponding (28).

The reward system is made up of various brainstructures. The central component is a neuronalpathway that interconnects structures in the mid-dle part of the brain (i.e., hypothalamus, ventraltegmental area) to structures in the front part ofthe brain (i.e., frontal cortex, limbic system)(15,16). A key part of this drug reward pathwayappears to be the mesocorticolimbic pathway(MCLP) (figure 2-l). MCLP is made up of theaxons of neuronal cell bodies in the ventraltegmental area projecting to the nucleus accum-bens, a nucleus in the limbic system. The limbicsystem is a network of brain structures associatedwith control of emotion and behavior, specificallyperception, motivation, gratification, and mem-ory. MCLP also connects the ventral tegmentalarea with parts of the frontal cortex (medialprefrontal cortex). Ventral tegmental neuronsrelease the neurotransmitter doparnine to regulatethe activity of the cells in the nucleus accumbensand the medial prefrontal cortex. Other parts ofthe reward system include the nucleus accumbensand its connections with other limbic structureslike the amygdala and hippocampus, as well as toother regions in the front part of the brain (i.e.,substantial innominata-ventral palladium). Thereare also connections from the nucleus accumbensdown to the ventral tegmental area. Finally, otherneuronal pathways containing different neuro-transmitters (i.e., serotonin, opioids, gamma aminobutyric acid (GABA), glutamate, peptides) regu-late the activity of the mesocorticolimbic dopa-rnine system and are also involved in mediatingthe rewarding properties of drugs of abuse.

These structures and pathways are thought toplay a role in the reinforcing properties of manydrugs of abuse, although the precise mechanismsinvolved in all drugs of abuse lack a thoroughdescription. The mesocorticolimbic dopamine

Chapter 2—Basic Concepts | 11

Figure 2-l—The Mesocorticolimbic Pathway

Frontal -—---cortex

Nucleus —accumbens

tegmental varea

The mesocorticolimbic pathway from the ventral tegmentalarea to the nudeus accumbens and the frontat cortex is a keycomponent of the brain reward system for drug reinforcement.SOURCE: Off Ice of Tdnobgy Assessment, 1993.

pathway appears to be critical in the rewardingproperties of stimulant drugs such as cocaine andamphetamines (15,16,29). Also, both the ventraltegmental area and the nucleus accumbens appearto be important for opiate reward (7,15,16), whilethese same structures and their connections toother limbic areas, like the amygdala, may play arole in the rewarding properties of barbituratesand alcohol (15,16,20). Further details about thebrain areas involved in the rewarding propertiesof various drugs of abuse are provided in chapter 3.

NEUROADAPTIVE RESPONSESExposure to drugs causes changes in the brain.

These changes are alterations in neurochemicalmechanisms related to the pharmacological ac-tion of a given drug. Often the change representsa compensatory adjustment in the brain to returnthe balance of activity back to normal after initialexposure to the drug. Most drugs of abuse involvecomplex actions in the brain resulting in a varietyof behavioral effects. Often, the type of neu-roadaptive response that occurs to a drug isopposite to its acute effects. Thus, the positivereinforcing properties of drugs are replaced by thenegative reinforcing properties of withdrawal.This indicates that neuroadaptive responses can

have motivational consequences that contributeand play a role in an individual’s subsequentdrug-taking behavior. The specific details of thebiological mechanisms that underlie these phe-nomena are not completely understood, but recentadvances in neuroscience research have begun tounravel how neuroadaptive responses manifestthemselves for various drugs of abuse. As with theimmediate rewarding properties of these drugs,some evidence suggests that there may be com-mon underlying mechanisms to the neuroadaptiveresponses related to reward mechanisms of vari-ous drugs of abuse (2). What follows is a generaldescription of neuroadaptive responses. Specificdetails of possible biological mechanisms associ-ated with the neuroadaptive responses of variousdrugs are provided in chapter 3.

| ToleranceTolerance develops to a drug when, following

a prolonged period of use, more of the drug isrequired to produce the same effect (10,14).Tolerance occurs with many types of drugs. It isa common, but unnecessary, characteristic ofdrugs of abuse. There are two types of tolerance:dispositional (pharmacokinetic) and pharmaco-dynamic.

DISPOSITIONALDispositional tolerance develops when the

amount of drug reaching active sites in the brainis reduced in some way. Generally, this arisesfrom an increased breakdown of the drug or achange in its distribution in the rest of the body.Thus, more drug must be taken to achieve thesame blood levels or concentrations at the activesites in the brain.

PHARMACODYNAMICThis form of tolerance represents a reduced

response of the brain to the same level of drug. Itdevelops during the continued and sustainedpresence of the drug. It may be that the mecha-nism of adaptation may differ from drug to drugand depend on the original mechanism of action


of a given drug. The net effect is that more drugis required to overcome this new neuronal adapta-tion to produce an equivalent pharmacologiceffect.

Although dispositional tolerance represents acomponent of tolerance to some drugs (e.g.,alcohol, barbiturates), in most cases much or allof the tolerance that develops to drugs withsignificant abuse potential can be attributed topharmacodynamic tolerance (10,14). Tolerancecan contribute to drug-taking behavior by requir-ing that an individual take larger and larger dosesof a drug to achieve a desired effect.

I DependenceLike pharmacodynamic tolerance, dependence

also refers to a type of neuroadaptation to drugexposure. Dependence differs in that, with pro-longed use of a drug, cells in the brain adapt to itspresence such that the drug is required to maintainnormal cell function. On abrupt withdrawal of thedrug, the neuron behaves abnormally and awithdrawal syndrome ensues. Generally, the with-drawal syndrome is characterized by a series ofsigns and symptoms that are opposite to those ofthe acute effects of the drug. For example, onwithdrawal, sedative drugs produce excitationand irritability. Conversely, stimulants produceprofound depression on withdrawal.

The magnitude of the withdrawal syndromevaries from drug to drug. With some drugs verymild withdrawal occurs, whereas with others(e.g., alcohol, barbiturates) the withdrawal syn-drome can be so severe that it is life-threatening.No matter the severity of the withdrawal syn-drome, its existence can create a craving or desirefor the drug and dependence can play a verystrong role in recurrent patterns of relapse, inmaintaining drug-seeking behavior to forestallthe withdrawal syndrome, and in the need toreestablish some sense of normalcy.

| Residual Tolerance and Dependence In general, expression of tolerance and depend-

ence has been considered to be rate-limited in thattolerance to most drugs gradually dissipates withtime as the brain readapts to the disappearance ofthe drug and withdrawal peaks within hours ordays after discontinued use and then dissipates.However, substantial evidence indicates thatthere may be persistent or residual neuroadapta-tion that lasts for months or years (10,27). Forexample, craving and drug-seeking behavior havebeen reported to last for years with nicotine,alcohol, and cocaine suggesting some residualeffect of drug use that may or may not dissipatewith time. Moreover, there is a phenomenon thatcharacterizes drug-dependent individuals. Specif-ically, with repeated cycles of abstinence andreinitiation of drug use, the time required to elicitdrug dependence grows shorter and shorter.Furthermore, there is evidence that the adminis-tration of naloxone, a drug that blocks the actionsof opiates, may elicit a withdrawal syndrome inindividuals who have abstained from use forextensive periods of time. These data indicate thatsome residual neuroadaptive changes induced bydrugs persist for as yet undefined periods of time.Little information is available about the mecha-nisms involved in this effect, but it is clear thatresidual neuroadaptive changes may persist forextended periods of time in former drug users andthat they may account for the striking relapses thatoccur in long-term abstinent drug-dependentindividuals.

I SensitizationSensitization occurs when the effects of a given

dose of a drug increase after repeated administra-tion. Thus, sensitization is the opposite of toler-ance. Sensitization to a drug’s behavioral effectscan play a significant role in supporting drug-taking behavior.

Chapter 2–Basic Concepts | 13

ABUSE LIABILITYThe abuse liability of a drug is a measure of the

likelihood that its use will result in drug addic-tion. While many factors ultimately play a role inan individual’s drug-taking behavior, the abusepotential of a drug is related to its intrinsicrewarding properties and the neuroadaptive re-sponses that result from prolonged use. Drugs canbe tested and screened for their abuse liability.The conceptual framework to screen drugs fortheir abuse potential is virtually the same for alldrugs: opiates, stimulants, depressants, hallucino-gens, and inhalants (l). The criteria that can beevaluated to classify a drug as having significantabuse potential are: pharmacological equivalenceto known drugs of abuse, demonstration ofreinforcing effects, tolerance, and physical de-pendence. The capacity to produce reinforcingeffects is essential to any drug with significant abuse potential, whereas tolerance and physicaldependence most commonly occur but are notabsolutely required to make such a determination.

Testing new pharmaceuticals for their abusepotential is an important step in new drugdevelopment. The emphasis of many major phar-maceutical firms today is on the development ofnew and safer drugs for pain reduction and in thedevelopment of psychoactive compounds to treatbrain disorders. In particular, scientific strides inunderstanding the brain, neurological disease,psychiatric disturbances, and aging are fuelingresearch into treatment of brain disorders. As suchpsychoactive compounds become available, theymust be screened for abuse potential. The abuseliability assessment of new products is not simplyat the discretion of the manufacturer. As dis-cussed in appendix A, various Federal regulatorylaws mandate such testing and Federal regulatoryagencies are charged with seeing that testing iscarried out.

Animal models are generally used to screen forthe abuse potential of new drugs in earlier stagesof drug development or to evaluate abuse poten-tial in drugs that cannot be readily studied in

humans (l). Laboratory methods for abuse poten-tial evaluation in humans are also well developed,and this is an area of active research(8). However,factors such as the heterogeneity of drug usingpopulations, the use of multiple drugs, and theother biological, social, and environmental fac-tors involved in human drug use make humanstudies complex.

At first glance, it would seem impossible tomimic in an animal the highly complex syndromeof drug abuse in humans. However, paradoxi-cally, the apparent limitations of animal modelsare actually their strengths. Specifically, thesimplicity of an animal model obviates theproblems inherent in the complexity of humans:the experimenter has strict control of environ-mental factors, drug use experience and patterns,and individual differences that permit study of thepharmacological and biological mechanisms as-sociated with the development of addiction po-tential. Thus, the use of animal models permitsthe highly complex syndrome of human drugaddiction to be dissected into separate compo-nents without the intrusion of a series of con-founding variables found in humans.

In terms of the validity of animal models as ameans of studying human drug addiction, anexcellent correlation exists between predictingthe abuse liability of specific classes of drugs inanimals and humans (12). However, it must berecognized that animal models are not perfectand, in fact, there are examples of drugs thatproved to have significant abuse potential inhumans, whereas the preclinical testing in ani-mals revealed relatively minimal abuse potential(6,10,14). Thus, the ultimate answer to the issueof whether a drug has significant abuse potentialis long-term experience with the drug once it hasbecome available, either legally or illegally.Nevertheless, animal models serve as the onlypractical means of initially screening drugs forabuse liability and have proven to be the mosteffective means of detecting whether there islikely to be a problem in humans.


Self=AdministrationThe predominant feature of all drugs with

significant addiction-producing properties is thatthey are self-administered (3,5,9,11). In fact,self-administration of a drug to the point when thebehavior becomes obsessive and detrimental tothe individual is the primary criterion for classify-ing a drug as having significant potential foraddiction. In addition to self-administration, an-other predictor of drug addiction is the notion ofcraving and the tendency to relapse or increaseuse during withdrawal (6, 10,14). Although crav-ing is a difficult term to quantify, once a drug isvoluntarily or involuntarily withdrawn, the desireto take it can play a role in the relapse to substanceabuse. As previously mentioned, the reinforcingproperties of the drug underlying craving maybeshifted from the pattern established during theinitial, early phase of drug addiction. Specifically,the drug may have initially been self-adminis-tered for its pleasurable effects but may eventu-ally be self-administered to relieve the discomfortassociated with withdrawal. Thus, the primarymotivation for using the drug can be that theindividual needs the drug to function normally.

Animals can be readily trained to self-administer drugs (6). Which experimental tech-nique is used depends on the class of compounds,a drug’s normal route of administration in hu-mans, and methodological concerns (e.g., solubil-ity of the drug). While the reasons animals initiatedrug-seeking behavior are dictated by the experi-mental situation, rather than intrinsic disposi-tional factors as in humans, the pattern of use onceestablished fulfills all of the criteria of drugaddiction: compulsive drug-seeking behavior tothe point of detrimental effects on the animal andenhanced attempts of self-administration duringwithdrawal.

The technique of self-administration is a pow-erful tool and provides a good indication of theabuse liability of new or unknown drugs (l). Forexample, substitution studies can be used todetermine whether, and over what dosage ranges,

drugs have reinforcing effects. In addition, theefficacy of drugs as reinforcers can be evaluatedusing the amount of work animals will perform toobtain drug injections or how they make selec-tions between drug reinforcers. By making com-parisons of the self-administration rates of un-known compounds with known standard refer-ence drugs, it is often possible to estimate thereinforcing property of the drug relative to thestandard. Thus, by using self-administration tech-niques, one can assess the relative reinforcingstrengths of a drug and also examine the behav-ioral, physiological, and biological factors thatlead to sustained self-administration.

I Drug DiscriminationDrug discrimination is another tool used in the

assessment of abuse liability of drugs in animals(3,6). Drug discrimination refers to the perceptionof the effects of drugs. Specifically, animals orhumans trained to discrimin ate a drug fromplacebo show a remarkable ability to distinguishbetween the effects of the drug from other drugspossessing different properties. The proceduresalso permit a determination of whether the animalconsiders the drug to be the pharmacologicalequivalent of another drug. Pharrnacologicalequiv-alence refers to the fact that drugs of a particularclass, such as opiates, stimulants, and depres-sants, produce a unique series of effects on thebrain and other organs that collectively constitutetheir pharmacological profile. Thus, althoughdrugs may vary considerably in their chemicalstructure, similar pharmacological effects indi-cate specifically how they actually interact withand influence the behavior of the intact organism.While animals cannot express whether a drug’ssubjective effects are similar or dissimilar toanother, various behavioral experiments can beused to determine whether an animal perceivesdrugs to be pharmacologically dissimilar orequivalent. For example, animals can clearlydistinguish opiates from stimulants or other

Chapter 2–Basic Concepts I 15

depressants, but may be unable to distinguish oneopiate of the same type from another.

| Dependence and ToleranceDependence and tolerance can readily be

induced in animals by either volitional or passivemeans (13,14). Specifically, using a self-administration model, animals often will developtolerance and dependence characterized by in-creased amounts of drug self-administration and/or enhanced rates of self-administration. Follow-ing abrupt withdrawal of the drug, a withdrawalsyndrome will often develop and, if given theopportunity, self-administration rates will beincreased. Alternatively, it is often easier toinduce tolerance and physical dependence pas-sively by injecting large amounts of drug intoanimals for prolonged periods of time. In thiscase, neuroadaptation occurs quickly and predict-ably. This technique has the advantage that theexperimenter can exercise complete control ofdoses and times required to produce tolerance anddependence. In either case, it is possible to induceneuroadaptation in animals that can then beexperimentally manipulated. Furthermore, sincethe understanding of the neuroadaptive changesthat take place during the development of toler-ance and physical dependence are poorly under-stood in humans, animal models offer a uniqueopportunity to carry out experiments designed toaddress these issues.

I Interpretation of Results in Animals andthe Concept of Thresholds

Once a drug has been classified as havingsignificant abuse potential, two central questionsremain: first, does this information pertain tohumans; and, second, can one rate the relativeabuse potential of drugs in animals (e.g., Doesdrug A have five times the abuse liability of drugB?). with regard to the frost point, results fromanimal testing generally have been excellentpredictors of abuse liability of drugs in humans,but a small number of exceptions mandate that

final drug testing be carried out in humans.Nevertheless, animal testing is an accepted pre-dictor of abuse potential in humans and must becarried out to provide the basis for additionalscreening in humans.

In terms of rating the abuse liability of drugs inanimals, the degree of abuse liability that can beexpected from a drug of abuse can be determinedusing the animal testing procedures outlinedabove. For example, by comparing the degree towhich a drug satisfies the criteria outlined above,such as the amount of work that will be performedto self-administer the drug and the strength of thephysical dependence, general conclusions aboutthe abuse potential of an unknown drug by eithercomparison to drugs of a similar class or differentclasses of drugs can be made.

while tests show that a drug has abuse poten-tial, the problem it poses in humans ultimatelydepends on the overall effects of the drug and theextent to which self-administration of the drugrepresents a problem to the individual or society.Relative abuse potential and its severity must beconsidered in terms of the consequences not onlyto the person, but also in the societal andenvironmental context in which it occurs.

ROLE OF LEARNINGAnother significant contributing force in drug

abuse is the learning that can occur during anindividual’s drug-taking activity (18,23).

In addition to producing pleasant feelings inthe user and having rewarding properties, drugs ofabuse produce changes in numerous organ sys-tems such as the cardiovascular, digestive, andendocrine systems. Both the behavioral andphysiological effects of a drug occur in thecontext of an individual’s drug-seeking anddrug-using environment. As a result, there areenvironmental cues present before and during anindividual’s drug use that are consistently associ-ated with a drug’s behavioral and physiologicaleffects. With repetition the cues become condi-tioned stimuli, that on presentation, even in the


absence of the drug, evoke automatic changes inorgan systems and behavioral sensations that theindividual may experience as drug craving. Thisis analogous to Pavlov’s classical conditioningexperiments in which dogs salivate on the cue ofa bell, following repeated pairing of food presen-tation with a ringing bell. Evidence for this effectis seen in numerous studies showing that animalsseek out places associated with reinforcing drugsand that the physiological effects of drugs can beclassically conditioned in both animals and hu-mans (12). Thus, exposure to environmental cuesassociated with drug use in the past can act as astimulus for voluntary drug-seeking behavior. Ifthe individual succeeds in finding and taking thedrug, the chain of behaviors is further reinforcedby the drug-induced rewarding feelings and theeffects of the drug on other organ systems (18).Drug conditioning can help explain the fact thatmany drug abusers often return to environmentsassociated with drug use, even after being coun-seled not to. The effects of the environmentalstimuli can be similar to the priming effects of adose of the drug.

Also, it has long been known that conditioningoccurs in relation to the withdrawal effects ofdrugs (26). It was observed that opiate addictswho were drug free for months and thus shouldnot have had any signs of opiate withdrawal,developed withdrawal symptoms (e.g., yawning,sniffling, tearing of the eyes) when talking aboutdrugs in group therapy sessions. This phenome-non, termed conditioned withdrawal, results fromenvironmental stimuli acquiring the ability,through classical conditioning, to elicit signs andsymptoms of pharmacological withdrawal. Con-ditioned withdrawal can also play a role in relapseto drug use in abstinent individuals. The emer-gence of withdrawal symptoms as a result ofexposure to conditioned cues can motivate anindividual to seek out and use drugs.

Studies have also demonstrated that, onceestablished, conditioned associations are difllcultto reverse (23). In theory, repeated presentation ofthe environmental cues, without the drug, should

extinguish the conditioned association. Animalstudies indicate that extinction is difficult toachieve and does not erase the original learning.As a result, once established, the extinction iseasily reversed. Animal studies examining drugconditioning have found that various aspects ofextinguished responses can either be reinstatedwith a single pairing of the drug and environ-mental cue, can be reinstated with a single dose ofdrug in the absence of the environmental cue, orcan spontaneously recover (23).

The biological mechanisms underlying condi-tioned drug effects are just beginning to bedescribed. Recent evidence links the mesocorti-colimbic system to these effects. Studies havefound increased release of dopamine in thenucleus accumbens associated with anticipatedvoluntary alcohol consumption (18,19,24,25).Other studies have presented evidence that de-struction of MCLP blocks the conditioned rein-forcing effects of opiates (4,21,22). The excita-tory amino acid neurotransmitters may also playa role in drug conditioning effects. As the nameimplies, excitatory amino acids are a class ofneurotransmitter that act to stimulate neuronalactivity in the brain. These amino acids have beenimplicated in learning and memory. Injection ofa drug that blocks the activity of the excitatoryamino acids has been shown to block the development of conditioned amphetamine effects (23).Finally, there is evidence that genetic factors mayplay a role in the conditioning phenomena associ-ated with drug use (see ch. 4).

CHAPTER 2 REFERENCES1. Balster, R.L., “Drug Abuse Potential Evaluation

in Amin”Anunak,’ British Journal of addiction 86: 1549-1558, 1991.

2. Beitner-Johnson, D., Guitart, X., and Nestler, E.J.,“Common Intracellular Actions of Chronic Mor-phine and Cocaine in Dopaminergic Brain Re-ward Regions, ” P.W. Kalivas, and H.H. Samson(eds.), The Neurobiology of Drug and AlcoholAddiction, Annals of the American Academy ofSciences 654:70-87, 1992.

Chapter 2–Basic Concepts | 17

3. Bigelow, G.E., andPreston, K. L., “DrugDiscrim-ination: Methods for Drug Characterization andClassification,’ NIDA Research Monograph #92:Testing for Abuse Liability of Drugs in Humans,U.S. Department of Health and Human ServicesPub. No (ADM) 89-1613, M.W. Fishman, andM.K. Mello (eds.) (Washington, DC: U.S. Gov-ernment Printing Office, 1989).

4. Bozarth, M.A., and Wise, R. A., “IntracranialSelf-Administration of Morphine Into the VentralTegmental Area of Rats,” Life Sciences 28:551-555, 1981.

5. Brady, J. V., “Issues in Human Drug AbuseLiability Testing: Overview and Prospects for theFuture,” NIDA Research Monograph #92: Test-ing for Abuse Liability of Drugs in Humans, U.S.Department of Health and Human Services Pub.No (ADM) 89-1613, M.W. Fishman, and M,K.Mello (eds.) (Washington, DC: U.S. GovernmentPrinting Office, 1989).

6. Brady, J.V., and Lucas, S.E. (eds.), NIDA Re-search Monograph #52: Testing Drugs for Physi-cal Dependence Potential and Abuse Liability,U.S. Department of Health and Human ServicesPublication No. (ADM) 84-1332 (Washington,DC: U.S. Government Printing Office, 1984).

7. Di Chiara, G., and North, R. A., “Neurobiology ofopiate Abuse “ Trends in Pharmacological Sci-ence, 13:185 -;93, 1992.

8. Fischman, M.W,, and Mello, N.K. (eds.), NIDAResearch Monograph #92: Testing for AbuseLiability of Drugs in Humans, U.S. Department ofHealth and Human Services Pub. No (ADM)89-1613 (Washington, DC: U.S. GovernmentPrinting Office, 1989).

9. Henningfield, J.E., Johnson, R.E., and Jasinski,D. R., “Clinical Procedures for the Assessment ofAbuse Potential,” Methods of Assessing theReinforcement Properties of Drugs, M.A, Bozarth(cd.) (Berlin: Springer-Verlag, 1987).

10. Jaffe, J.H., “Drug Addiction and Drug Abuse,”The Pharmacological Basis of Therapeutics, A.G.Gilman, T.W. Rail, A.S. Nies, et al.(eds.) (NewYork, NY: Pergammon Press, 1990).

11. Jasinski, D. R., and Henningfield, J.E., “HumanAbuse Liability Assessment by Measurement ofSubjective and Physiological Effects,” NIDAResearch Monograph #92: Testing for Abuse

Liability of Drugs in Humans, U.S. Department ofHealth and Human Services Pub. No (ADM)89-1613, M.W. Fishman, and M.K. Mello (eds.)(Washington, DC: U.S. Government PrintingOffice, 1989).

12. Johanson, C., Woolverton, W. L., and Schuster,C.R., “Evaluating Laboratory Models of DrugDependence,” Psychopharmacology: The ThirdGeneration of Progress, H. Meltzer (cd.) (NewYork, NY: Raven Press, 1987).

13. Kalant, H., “Behavioral Criteria forTolerance andDependence,’ The Bases of Addiction, J. Fishman(cd.) (Berlin: Dahlem Konferenzen, 1988).

14. Kalant, H., ‘‘The Nature of Addiction: An Analy-sis of the Problem,” Molecular and CellularAspects of the Drug Addictions, A. Goldstein (cd.)(New York, NY: Springer Verlag, 1989).

15. Koob, G. F, “Drugs of Abuse: Anatomy, Pharma-cology and Function of Reward Pathway s,’Trends in Pharmacological Science 13:177-183,1992.

16. Koob, G. F., and Bloom, F. E., “Cellular andMolecular Mechanisms of Drug Dependence,”Science 242:715-723, 1988.

17. Liebman, J.M., and Cooper, S.J. (eds.), TheNeuropharmacological Basis of Reward (NewYork, NY: Claredon Press, 1989).

18. O’Brien, C. P., Childress, A.R., McLelland.lan, A.T., etal., “Classical Conditioning in Drug-DependentHumans,” P.W. Kalivas, and H.H. Samson (eds.),The Neurobiology of Drug and Alcohol Addiction,Annals of the American Academy of Sciences654:400415, 1992.

19. Post, R. M., Weiss, S.R.B., Fontana, D., et al.,“Conditioned Sensitization to the PsychomotorStimulant Cocaine,” P.W. Kalivas, and H.H.Samson (eds.), The Neurobiology of Drug andAlcohol Addiction, Annals of the American Acad-emy of Sciences 654:386-399, 1992.

20. Samson, H.H., and Harris, R.A., “Neurobiologyof Alcohol Abuse,” Trends in PharmacologicalScience 13:206-211, 1992.

21. Shippenberg, T. S., Herz, A,, and Spanagel, R.,“Conditioning of Opioid Reinforcement: Neu-roanatomical and Neurochemical Substrates,”P.W. Kalivas, and H.H, Samson (eds.), TheNeurobiology of Drug and Alcohol Addictions,


Annals of the American Academy of Sciences654:347-356, 1992.

22. Spyraki, C., Fibiger, H. C., and Phillips, A.G.,“Attenuation of Heroin Reward in Rats byDisruption of the Mesolimbic Dopamine Sys-tem,” Psychopharmacology 79:278-283, 1983.

23. Stewart, J., “Neurobiology of Conditioning toDrugs of Abuse,” P.W. Kalivas, and H.H. Samson(eds.), The Neurobiology of Drug and AlcoholAddiction, Annals of the American Academy ofSciences 654:335-346 , 1992.

24. Vavrousek-Jakuba, E., Cohen, C.A., and Shoe-maker, W.J., “Ethanol Effects of CNS DopamineReceptors: In Vivo Binding Following VoluntaryEthanol Intake in Rats,” C.A. Narnajo, and E.M.Sellers (eds.), Novel Pharmacological Interven-tions for Alcoholism (New York NY: Springer-Verlag, 1990).

25. Weiss, F., Herd YL., Ungerstedt, U., et al.,“Neurochemica.1 Correlates of Cocaine and Etha-

nol Self-Administration,’ P.W. Kalivas, and H.H.Samson (eds.), The Neurobiology of Drug andAlcohol Addiction, Annals of the American Acad-emy of Sciences 654:220-241, 1992.

26. Wikler, A., “Recent Progress in Research on theNeurophysiological Basis of Morphine Addic-tion,” American Journal of Psychiatry 105:329-338, 1948.

27. Wise, R. A., “The Role of Reward Pathways in theDevelopment of Drug Dependence,” Pharmacolo-gical Therapeutics 35:227-263, 1987.

28. Wise, R.A., Bauco, P., and Carlezon, W.A.,“Self-Stimulation and Drug Reward Mechanisms,”P.W. Kalivas, and H.H. Samson (eds.), TheNeurobiology of Drug and Alcohol Addiction,Annals of the American Academy of Sciences654:192-198, 1992.

29. Woolverton, W. L., and Johnson, K. M., “Neurobi-ology of Cocaine Abuse,” Trends in Pharmacol-ogical Science 13:193-200, 1992.

TheNeuropharmacology

of Drugsof Abuse 3

rugs of abuse interact with the neurochemical mecha-nisms of the brain. Some of these interactions aredirectly related to the reinforcing properties of a drug,while others are related to other effects associated with

the drug. As in other areas of neuroscience, the level ofunderstanding about these interactions and the mechanismsinvolved has increased tremendously over the last decade. Thefundamentals of information processing in the brain and howpsychoactive drugs can alter these processes are being eluci-dated. For drugs of abuse, certain commonalities have begun toemerge. While drugs of abuse have a wide range of specificindividual actions in the brain, there is growing evidence thattheir reinforcing properties may result from a shared ability tointeract with the brain’s reward system. For each drug of abuse,this action, coupled with its actions in other areas of the brain,contributes to the overall behavioral effect the drug produces. Insome cases, the relationship of a drug’s neurochemical action andthe behavioral effects it produces have been clearly elucidated,while in others much remains to be learned.

This chapter describes how drugs of abuse affect neurochem-ical activity and the mechanisms that may underlie the character-istics contributing to and determining a drug’s abuse potential,namely, their reinforcing affects, the neuroadaptive responsesassociated with them, and the development of withdrawalsymptoms. A brief summary of basic neuropharmacology isprovided to give general background information on how drugswork in the brain.

, 0I

19


NEUROPHARMACOLOGYNeurons are the cells that process information

in the brain. Neurotransmitters are chemicalsreleased by neurons to communicate with otherneurons. When a neuron is activated it releases aneurotransmitter into the synapse, the gap be-tween two neurons (see figure 3-l). The mol-ecules of the neurotransmitter move across thesynapse and attach, or bind, to proteins, calledreceptors in the outer membrane of an adjacentcell. Once a neurotransmitter activates a receptor,it unbinds from the receptor and is removed fromthe synapse. This is done either by the neurotrans-mitter being taken back up into the neuron thatreleased it (a process called reuptake) or by beingchemically broken down. Usually the axon termi-nal is the part of the neuron that releasesneurotransmitters into the synapse, and the den-drites and cell body are the areas of the neuronthat contain receptors that form synapses with theaxons of other neurons.

For each neurotransmitter in the brain, there arespecific receptors to which it can attach. Bindingby the neurotransmitter activates the receptor,which can have different effects depending on thereceptor. Receptors can be linked to a variety ofmembrane and cellular mechanisms that areturned on or off by the activation of the receptor.Some receptors open or close ion channels (i.e.,for charged molecules such as potassium, sodium,calcium, or chloride) in the membrane of the cell.These channels regulate the flow of ions in andout of the cell. The relative concentration of ionsbetween the inside and outside of a neuron iscrucial in the activity of the neuron. Otherreceptors activate or inhibit intracellular mecha-nisms called second messengers. There are anumber of different second messengers thatcontrol various aspects of cellular activity.

A neuron can have thousands of receptors forseveral different neurotransmitters. Some neuro-transmitters activate neurons (excitatory neuro-transmitters), while others decrease neuronalactivity (inhibitory neurotransmitters). Sometimes

Figure 3-l—The Synapse and AssociatedStructures

M(Nerve impulse

v

Neurotransmitters ReceptorsReceiving cell


a receptor for one neurotransmitter can affect areceptor for another neurotransmitter. In suchcase, the receptors are biochemically coupled: theactivation of one modulates the function of theother, either increasing or decreasing its activity.A neuron can also have receptors for the neuro-transmitter it releases; these are usually locatednear the site where the neurotransmitter is re-leased into the synapse. Such receptors are actedon by the neuron’s own neurotransmitter toregulate the release of the neurotransmitter. Thus,these autoreceptors, as they are called, act as afeedback mechanism to regulate a neuron’s activ-ity. The activity of a neuron will be determined bythe cumulative activity of all of its variousreceptors. Activation of a neuron generates anelectrical impulse inside the neuron that travelsfrom the cell body, down the axon, to the axonterminal, where the impulse causes the release ofneurotransmitter into the synapse.

While receptors are specific for a neurotrans-rnitter, there may be a variety of receptor sub-

Chapter 3-The Neuropharmacology of Drugs of Abuse I 21

types, linked to different cellular mechanisms,that all respond to the same neurotransmitter. Inthis way one neurotransmitter can have diverseeffects in different areas of the brain. In addition,neurons are connected to different circuits in thebrain, further accounting for diverse effects.Many chemicals have been identified as neuro-transmitters, among them dopamine, norepineph-rine, serotonin, acetylcholine, various amino acids,and peptides. As discussed in chapter 2, some ofthese are of particular relevance to the rewardingproperties of drugs of abuse.

Psychoactive drugs alter these normal neuro-chemical processes. This can occur at any level ofactivity including mimicking the action of aneurotransmitter, altering the activity of a recep-tor, acting on the activation of second messen-gers, or directly affecting intracellular processesthat control normal neuron functioning.

In order to have these affects, a drug must enterthe brain, by diffusing from the circulatory systeminto the brain. Routes of administration refers tothe methods used to deliver a drug into thebloodstream. The route of administration affectshow quickly a drug reaches the brain. In addition,the chemical structure of a drug plays an impor-tant role in the ability of a drug to cross from thecirculatory system into the brain. The four mainroutes of administration for drugs of abuse areoral, nasal, intravenous, and inhalation. With oralingestion, the drug must be absorbed by thestomach or gut, which usually results in a delaybefore effects become apparent, and must passthrough the liver where it can be chemicallybroken down. Using the nasal route, effects areusually felt within 1 to 3 minutes, as the capillaryrich mucous membranes of the nose rapidlyabsorb substances into the bloodstream. Intrave-nous administration produces effects in 1/2 to 2minutes and is slowed only by detour backthrough the lungs that venous blood must take toreach the brain. Lastly, the inhalation methodbypasses the venous system because the drug isabsorbed into the arterial blood flow, which goesdirectly from the lungs to the heart and then to the

brain. As a result, effects are felt within 5 to 10seconds, making inhalation the fastest route ofadministration. The route of administration of adrug can determine the potency and efficacy thedrug will have on affecting brain activity. In somecases, the route of administration can also con-tribute to the abuse potential of a drug.

DRUGS OF ABUSE

I StimulantsAs the name implies, stimulant drugs have an

energizing effect that promotes an increase inpsychological and/or motor activity. Stimulantssuch as cocaine and the amphetamines have theirmost pronounced effect on the monoamine neuro-transmitters (i.e., dopamine, serotonin, norep-inephrine, and epenephrine) in the brain. Theyalso stimulate the physiological mechanisms thatare triggered in stressful situations (the ‘‘fight orflight” response) via activation of the sympa-thetic nervous system. These include increases inheart rate and blood pressure and the release ofvarious hormones. The arousing and euphoriceffects associated with these drugs are associatedwith these various actions. Other stimulant drugsare caffeine and nicotine. These drugs havevarious mechanisms of action, but their net effectis to stimulate central nervous system (CNS)activity.

COCAINECocaine is found in the leaves of the Erythrox-

ylon coca plant, a large shrub indigenous to SouthAmerica. The compound is extracted from theleaves and is then processed into either paste,powder, or freebase form. The paste is the mostrudimentary, unrefined form. Additional process-ing of the paste by adding hydrochloric acidproduces cocaine powder (cocaine hydrochlo-ride). Cocaine powder is often administered vianasal insufflation (i.e., snorting). Freebase co-caine is the pure cocaine base released fromcocaine hydrochloride by further separation usingsimple chemicals such as ether or sodium hydrox-


ide. This freebase cocaine is easily absorbed intothe membranes of the relatively alkaline environ-ment of the body. The well-known “crack”cocaine is simply baking soda and water mixedwith the base to create a solid form of freebasecocaine which is immediately and completelyabsorbed by the body when smoked. The mostcommon routes of administration for cocaine aresmoking and snorting although the intravenousroute is also used and is often preferred by thosewho also inject other drugs, such as opiates (45).

In humans, cocaine produces an elevation inmood and a sense of increased energy andalertness. This can include an improvement inconcentration and attention, a reduction in thesense of fatigue and performance decrementcaused by sleep deprivation, appetite suppression,and an increase in libido. The toxic effects of highdoses of cocaine include delirium, seizures,stupor, cardiac arrhythmias, and coma. Seizurescan result in sustained convulsions that stopbreathing.

Acute administration—The most prominentpharmacological effect of cocaine is to block thereuptake of dopamine back into the presynapticterminal once it has been released from a neuronterminal (61), resulting in increased levels ofdopamine at its synapses in the brain (see figure3-2). The specific uptake site for dopamine hasbeen identified and cocaine’s actions on themechanism that transports dopamine back intothe neuron is an active area of research. Within thebrain mesocorticolimbic pathway (MCLP), levelsof dopamine increase in the synapses between theterminals of the neurons projecting from theventral tegmental area and the neurons in thenucleus accumbens and medial prefrontal cortex(60,62). In addition to blocking dopamine reup-take, cocaine also blocks the reuptake of norep-inephrine and serotonin (62).

The acute behavioral effects of cocaine are theresult of these neurochemical actions. The acutereinforcing properties of cocaine are due to itscapacity to enhance the activity of dopamine inMCLP. As with most neurotransmitters, dopa-

rnine has a number of receptor subtypes distrib-uted in different brain areas. The reinforcingproperties of cocaine are mediated via dopamineactivation of at least two of these, the DI and D2

dopamine receptor subtypes (39,62), and morerecently there is evidence for an action at D3 re-ceptors (12). The increase in dopamine activityvia D2 and D1 receptors is also important in theother behavioral effects of cocaine (62). The roleof cocaine’s actions on brain norepinephrine andserotonin uptake in its behavioral effects has notbeen clearly established (62).

Chronic administration-Chronic adminis-tration of cocaine activates a number of brainneurochemical compensatory mechanisms, thedetails of which are not completely understood.Both short- and long-term changes in the dynam-ics of neurotransmission following repeated co-caine administration have been observed in ex-periments. Results from animal studies indicatethat continued administration results in a sus-tained increase in dopamine levels within thesynapses of the nucleus accumbens (60). This isbelieved to be due to a decreased sensitivity ofdopamine autoreceptors, which regulate the re-lease of dopamine from the presynaptic terminal.In their normal state, these autoreceptors decreasethe amount of dopamine released into the syn-apse. Changes also seem to occur in the numberof postsynaptic receptors for dopamine, but theexact nature of these changes has yet to becharacterized. Both increases and decreases inreceptor numbers have been reported (62). Theexact effects of chronic cocaine administrationseem to vary among receptor subtypes andlocations.

A number of changes in the intracellularmechanisms, including second messenger sys-tems, involved in the activity of dopamineneurons in the ventral tegmental area and nucleusaccumbens have been described following chroniccocaine administration (10). The changes arethought to be due to alterations in the expressionof the genes that regulate and control the intracel-lular mechanisms. The net effect of these changes

— ..-

Chapter 3-The Neuropharmacology of Drugs of Abuse | 23

Figure 3-2-Cocaine’s Principal Action Mechanism

Dopamine terminal

\

Cooaine’s principal mechanism of action is to block the uptakeof dopamine into the presynaptic terminal. (Compare to figure3-l.)


is to reduce the capacity of ventral tegmentalneurons to transmit dopamine signals to theneurons in the nucleus accumbens. This couldrepresent a mechanism by which tolerance to therewarding properties of cocaine could developand could contribute to cocaine craving. Impor-tantly, these changes are lacking in other dopam-ine pathways not involved in drug reward. Similarchanges were observed following chronic mor-phine administration . These findings suggest thata common physiological response to chronicadministration of these drugs of abuse may exist.Further investigations are necessary to com-pletely characterize the changes that occur and todetermine whether they are typical for other drugsof abuse.

Finally, animal studies have shown that re-peated administration of cocaine causes changesin the levels of other neurotransmitters, mostnotably some of the peptide neurotransmitters.

These changes may result from alterations indopamine transmission that effect other areas ofthe brain. These secondary responses indicate thatthe neurochemical adaptive response to repetitivecocaine administration involves a complex inter-action between multiple neuronal pathways andneurotransmitter systems (62).

Matching the pharmacological profile, thebehavioral response to repeated cocaine adminis-tration is also complex. Results from animalstudies suggest that how the drug is administeredcan affect whether sensitization or toleranceoccurs. Intermittent administration of cocaine cantrigger sensitization to some of its specific motoreffects, such as stimulating levels of activity(61,62). Conversely, tolerance to these motoreffects develops when the drug is given continu-ously (62). While it is unclear whether tolerancedevelops to cocaine’s reinforcing effects, experi-mental evidence suggests that it does and subjec-tive reports from cocaine users that the euphoricactions of the drug diminish with repeated usesupport the notion (45,62). Increasingly, experi-mental evidence suggests that chronic cocaineadministration increases drug craving (36,42).

A withdrawal reaction occurs with the abruptcessation of cocaine administration after repeateduse. This reaction is marked by prolonged sleep,depression, lassitude, increased appetite, andcraving for the drug (61). In animal studies,cocaine withdrawal results in an increase in thelevel of electrical stimulation necessary to inducea rat to self-stimulate the brain reward system(40). This indicates that during cocaine with-drawal, the brain reward system is less sensitive.While the precise pharmacological mechanismunderlying this withdrawal is unknown, it issuspected that it relates to some hypoactivity indopamine functioning within the brain rewardsystem (40). Changes in the expression of genesthat control intracellular mechanisms (10) repre-sent a possible mechanism that could account forthis change and could contribute to the drugcraving associated with chronic cocaine use.Avoidance of the withdrawal reaction can be


another important determinant in continued co-caine use.

AMPHETAMINESAmphetamines (i.e., dextroamphetamine, meth-

amphetamine, phemetrazine) produce effects sim-ilar to cocaine (20). Amphetamine users describethe euphoric effects of the drug in terms indistin-guishable from those used by cocaine users and inthe laboratory, subjects cannot distinguish be-tween the subjective effects of cocaine andamphetamine (36). This is not to suggest thatcocaine and amphetamine have identical mecha-nisms of action or that under properly selectedexperimental conditions differences between theireffects cannot be demonstrated. For example,cocaine effects are relatively brief after intrave-nous injection, whereas those of methampheta-mine may last for hours (36). Oral ingestion is themost common route of administration of ampheta-mines, although intravenous injection, smoking,and nasal insufflation are also used.

Acute administration—Like cocaine, acuteamphetamine administration results in moodelevation and increased energy. In addition, theuser may experience feelings of markedly en-hanced physical strength and mental capacity.Amphetamines also stimulate the sympatheticnervous system and produce the physiologicaleffects associated with sympathetic activation.High doses of amphetamine produce a toxicsyndrome that is characterized by visual, audi-tory, and sometimes tactile hallucinations. Thereare also feelings of paranoia and disruption ofnormal thought processes. The toxic reaction toamphetarnines is often indistinguishable from anepisode of the mental disorder schizophrenia.

Not surprisingly, action of amphetamines issimilar to cocaine. The reinforcing properties ofthese drugs is due to their ability to enhancedopamine action in MCLP. However, whileamphetamines also block dopamine reuptake,their most significant action is to directly stimu-late the release of dopamine from neurons (61)(figure 3-3). Thus, unlike cocaine, which blocks

Figure 3-3-Amphetamines’ PrincipalAction Mechanism

r ‘- 7 7- ” - ” -

Nerve Impulse

\

‘ \Amphetamines

\ $ /“P

b \,■ ■ ■

IAmphetamines’ principal mechanismism of action is to stimulatethe release of dopamine from the presynaptic terminal.(Compare to figure 3-1.)


dopamine reuptake following normal release ofthe transmitter from the terminal, the ampheta-mine increase in dopamine activity is independ-ent of neuronal activity (61). As a result of thisdifference, amphetamines are more potent thancocaine in increasing the levels of dopamine inthe synapse. Amphetamines also directly stimu-late the release of norepinephrine, epinephrine,and serotonin from neurons. Among the ampheta-mines, the balance between their actions on thesedifferent neurotransmitter systems vary. Forexample, methylenedioxymethamphetamineMDMA) has a particularly potent effect on theserotonin system, which imbues this drug with apsychedelic effect.

Chronic administration—As with cocaine,both sensitization and tolerance to different ef-fects of amphetamines occur. Animal studieshave shown that intermittent administration of

Chapter &The Neuropharmacology of Drugs of Abuse | 25

amphetaminees results in sensitization to themotor stimulating effects (61). This sensitizationis thought to be due to an augmentation ofdopamine release after intermittent, repeated drugadministration. Tolerance to the euphoric effectsof amphetamine develops after prolonged, contin-uous use (45). Such tolerance is believed to becaused by depletion of stored neurotransmitters,especially dopamine, in the presynaptic terminalsas a result of the continued stimulation of releasefrom the stores by the drug. Drug craving isincreased with continued amphetamine use (36,42).Finally, a withdrawal syndrome, similar to co-caine’s, is produced with the cessation of amphet-amine administration after prolonged use.

CAFFEINECaffeine is the most widely used psychoactive

substance in the world (28,33). Surveys indicatethat 92 to 98 percent of adults in North Americaregularly consume caffeine, mostly in coffee ortea (28). Caffeine belongs to a class of compoundscalled methylxanthines, which act as CNS stimu-lants (49). The stimulating effects of caffeine aredue to its ability to block the receptors for theinhibitory neurotransmitter adenosine (49). Caf-feine blocks both the Al and A2 adenosinereceptor subtypes, having its more potent effecton the A 1 receptor (49). Adenosine inhibits therelease of various neurotransmitters, in particularthe excitatory amino acid glutamate. Therefore,caffeine blockade of adenosine receptors resultsin increased glutamate activity. Caffeine alsoincreases the levels of norepinephrine and sero-tonin, which contributes to the drug’s CNSstimulating effects (49). Caffeine’s effects ondopamine are unclear in that increases, decreases,or no change in the release of dopamine have beenobserved following caffeine administration invarious experiments (49).

In humans, caffeine has a general alertingaffect, and it has been shown to increase locomo-tor activity in laboratory animals (49). However,experimental evidence indicates that in humans

there is great individual variability in caffeine’seffects (49). These differences are linked todifferences in rates of caffeine absorption fromthe gastrointestinal system and metabolism in thebody. Age also seems to affect the response tocaffeine, in that older people show an increasedsensitivity to caffeine’s stimulating effects (49).This is particularly true of caffeine’s disruptiveeffects on sleep.

Acute administration-caffeine exhibits, atmost, weak reinforcing effects in animal self-administration experiments (28,33). The level ofresponding induced by caffeine is much less thanthat seen with other stimulants such as ampheta-mine and cocaine (33). In humans, experimentsdemonstrate that caffeine’s reinforcing actionsare also minimal and dose-dependent (28,33).Low doses are mildly reinforcing with subjectsreporting positive subjective effects, while higherdoses produce adverse effects. The results fromhuman studies indicate that reinforcement occursonly under certain conditions and not across allindividuals (28). The mechanism of caffeine’sreinforcing actions is unknown.

Chronic administration—Humans can de-velop tolerance to many of the physical manifes-tations of caffeine’s actions such as increasedheart rate and higher blood pressure and there isevidence that tolerance develops to its behavioralconsequences including alertness and wakeful-ness (28,33,49). In animals, tolerance develops tosome of caffeine’s behavioral effects such as thestimulation of locomotor activity (49).

A withdrawal syndrome has clearly and repeat-edly been demonstrated after the cessation ofchronic caffeine consumption (28,33,49). Changesin mood and behavior can occur with lethargy andheadache being the two most common symptomsof caffeine withdrawal (28). These changes maybe the result of a compensatory increase inadenosine receptors resulting from the chronicblockade by caffeine. However, more studies areneeded to confirm this possibility (49).


NICOTINEIt is generally accepted that while people

smoke tobacco for many reasons (e.g., social,cultural), the majority of people who smoketobacco do so in order to experience the psy-choactive properties of the nicotine contained inthe smoke (4,56). Furthermore, a significantproportion of habitual smokers become depend-ent on nicotine and tobacco smoking has all theattributes of drug use considered to be addicting(4,38). Nicotine activates one of the receptorsubtypes for the neurotransmitter acetylcholine(38,56). As a result, this receptor is called thenicotine receptor. The psychological effects ofnicotine are fairly subtle and include moodchanges, stress reduction, and some performanceenhancement (7).

When tobacco is smoked, nicotine is readilyabsorbed by the lungs. Studies of smokingpatterns have shown that habitual smokers tend tosmoke more efficiently, because they inhalelonger, have shorter intervals between puffs, andtake a greater number of puffs per cigarette thusincreasing the dose of nicotine they receive (38).Smokeless tobacco involves either chewing to-bacco leaves or placing tobacco between thecheek and gums. The blood nicotine level achievedusing smokeless tobacco can be comparable tothat achieved by smoking cigarettes. Because ofthe route of administration, however, blood nico-tine levels remain higher longer (45). Evidenceindicates that the diseases related to the use oftobacco may be caused by different constituentsof tobacco or tobacco smoke. For example,cardiovascular effects are related to carbon mon-oxide in the smoke, and the effects on the heartand various cancers are probably due to carcino-gens in the tobacco (36).

Acute administration—Nicotine stimulatesthe release of dopamine from dopamine neuronsin the MCLP (4,56). This results from activationof nicotine receptors that stimulate activity indopamine neurons in the ventral tegmental area.However, when compared to the effects ofcocaine or amphetamine, the nicotine increase in

dopamine release is modest, and as a result,nicotine is a comparatively weak reinforcer inanimal experiments (4,56). Nonetheless, nicotinereinforcing properties are thought to be the resultof this action. “Animal study results indicate thatactivation of nicotine receptors also stimulatesthe release of noradrenaline from neurons in thelocus ceruleus and may reduce serotonin activityin the hippocampus (4). However, the exactnature of these changes and the role they may playin the behavioral effects of nicotine is unclear.

Chronic administration—Tolerance devel-ops to many of the effects of nicotine and awithdrawal syndrome marked by irritability, anx-iety, restlessness, and difficulty in concentratingdevelops when tobacco use stops (4,36,45). Inaddition, a craving for tobacco, which maysubside in a few days, occurs (36). The pharma-cological mechanisms underlying these changesare unknown. Although animal studies havesuggested that chronic administration of nicotineincreases the number of nicotine receptors, themechanism that mediates this increase and thepossible involvement it plays in the tolerance andwithdrawal associated with nicotine remains to beclarified (4,56).

| PhencyclidinePhencyclidine (PCP) is representative of a

unique class of abused drugs that includes theanesthetic ketamine and other drugs similar toPCP. PCP was developed as an injectable anes-thetic in the 1950s. However, PCP anesthesia isquite dissimilar to that produced by typicalgeneral anesthetics (6,8). It produces a dissocia-tive state in which patients are generally unre-sponsive and perceive no pain. Patients areamnesic for the surgery and CNS depression seenwith other general anesthetics is absent. Deliriumthat often occurs on emergence from PCP anes-thesia curtailed PCP’s use as an anesthetic inhumans. It is still sometimes used as a veterinaryanesthetic but is no longer marketed in the UnitedStates.


At nonaesthetic doses PCP produces behav-ioral effects in common with several other drugsincluding amphetamines, barbiturates, opiates,and psychedelics (13). Given its wide range ofbehavioral effects, PCP’S broad neurochemicalaction in the brain is not surprising. PCP antago-nizes the actions of the excitatory amino acidneurotransmitter glutamate at the N-methyl-D-aspartate (NMDA) receptor, one of the receptorsubtypes for glutamate (8,37). Glutamate is foundthroughout the brain and increases the flow ofcalcium ions into cells to cause excitatory actions.The NMDA receptor controls the calcium ionchannel acted on by glutamate and binding ofPCP to the receptor blocks calcium entry into thecell. It is likely that the diverse behavioral effectsof PCP are due to the fact that glutamate is widelydistributed in the brain and regulates the activityof a number of other neurotransmitter systems.PCP also affects brain dopamine systems in wayssimilar to amphetamine (37).

The subjective effects of PCP administrationcan vary dramatically depending on a user’spersonality and a user may experience vastlydifferent reactions during different drug-takingepisodes (13). In most cases, low doses produceeuphoria, feelings of unreality, distortions oftime, space, and body image, and cognitiveimpairment. Higher doses produce restlessness,panic, disorientation, paranoia, and fear of death.As with its use as an anesthetic, PCP often causesamnesia to occur beginning immediately after thedrug is taken until its effects begin to wear off.PCP is often associated with violent behavior inusers but laboratory studies indicate that it doesnot increase aggressive behavior in animals (6). Infact, the bulk of evidence indicates that PCPdecreases aggression at most doses under mostexperimental conditions (6). The violence oftenassociated with PCP use is likely to be due to acombination of its multiple effects including itsability to block pain and its stimulant andpsychedelic actions.

Acute administration—In animal studies, PCPhas been shown to be a highly effective reinforcer

(6,13). From clinical reports of human PCP useand from animal studies, route of administrationappears to affect the self-administration rate.Intravenously delivered PCP has been establishedas a reinforcer in rats, dogs, and primates. OralPCP is rapidly established as a reinforcer inprimates but not in rats (13). In humans, the mostcommon route of administration of PCP issmoking.

The mechanism of action of PCP’S reinforcingeffects are unclear. Part of PCP’S behavioraleffects are similar to dopamine-stimulating drugslike amphetamine (37) and its administrationpotentates the sedating properties of alcohol andbarbiturates (6,13). As previously mentioned,PCP blocks the action of glutamate at the NMDAreceptor. All of these actions may be relevant tothe production of its reinforcing effects.

Chronic administration—Repeated PCP ad-ministration has been shown to produce toleranceto many of its effects in animals (6,13). Themagnitude of the tolerance, however, is less thanwhat is seen with most other drugs of abuse (13).Systematic studies of PCP tolerance in humanshave been few, but chronic PCP users report thatafter regular use they increase the amount of PCPsmoked by at least twice (13). Some evidencefrom animal studies also suggests that sensitiza-tion may develop to PCP under certain conditions(13).

A withdrawal syndrome occurs in animals thathave been chronically administered PCP (13). Itis characterized by signs of CNS hyperexcitabil-ity such as twitches, tremors, and increasedsusceptibility to seizures. Although PCP with-drawal syndrome can be reliably produced inanimals, a withdrawal syndrome in humans hasyet to be clearly identified (13). Symptoms ofdepression, drug craving, increased appetite, andincreased need for sleep have been reported tooccur between 1 week and 1 month after termina-tion of chronic PCP use (57). The lack of clearevidence of a PCP withdrawal syndrome inhumans may be due to the fact that the drug isusually not taken in large enough quantities


and/or not frequently enough to produce symp-toms (13).

The neurochemical mechanisms underlyingPCP tolerance and withdrawal are unknown.Both, direct PCP-induced alterations in NMDAreceptors and secondary changes in other neuro-transmitter systems as a result of altered gluta-mate activity could play a role.

| SedativesAlcohol, barbiturates, and benzodiazepines are

drugs that inhibit CNS activity. Many of the abuseinhalants appear to produce similar effects tothese sedative/depressant drugs. Although allthese drugs have different specific mechanismsof action in the brain, they all share the abilityto enhance the activity of the inhibitory aminoacid neurotransmitter gamma amino butyric acid(GABA). In some cases activation of inhibitorypathways in the brain, in turn, hampers otherinhibitory pathways. The effect of inhibiting aninhibitory pathway is often the net activation of abrain region. This mechanism of interfering withother inhibitory pathways is thought to play a rolein the abuse potential of these drugs.

ALCOHOLAlcohol differs from most other drugs of abuse

in that it has no known receptor system in thebrain (52). Alcohol affects a number of differentneurotransmitter systems through its action on themembranes of neurons and the ion channels,particularly those for calcium and chloride, thatlie within them (43). In general, alcohol inhibitsreceptors for excitatory neurotransmitters andaugments activity at receptors for inhibitoryneurotransrnitters (52). For example, alcoholenhances the activity of GABA by affecting ionchannels that are related to a subpopulation of theGABAA receptor subtype (figure 3-4) and de-creases the action of the excitatory amino acidneurotransmitter glutamate, through inhibition ofthe NMDA receptor (43,52,55). The net effect ofalcohol is to depress activity in the brain produc-ing its characteristic sedating and intoxicating

effects. A similar spectrum of effects is seen withbarbiturates and benzodiazepines.

Acute administration—In humans, acute con-sumption of alcohol produces a sense of wellbeing and mild euphoria and studies have shownthat animals will orally self-administer alcohol.Several lines of evidence have implicated dopam-ine, serotonin, GABA, and opioid peptides inalcohol reinforcement.

Results from several types of studies indicatethat dopamine is involved in the acute reinforcingeffects of alcohol. Drugs that block the activity ofdopamine reduce alcohol self-administraticm inrats (40,53). Also, depending on the dose, alcoholmay stimulate locomotor activity and produce anincrease in dopamine levels in the nucleus accum-bens (60). Finally, data from genetic models ofalcohol preference, in which a strain of rats is bredto have a higher than normal preference forself-administering alcohol, indicate that alcohol-induced release of dopamine is higher in thealcohol-preferring rats than in nonpreferring rats(60). These data suggest that activation of theMCLP is involved in the reinforcing actions ofalcohol. However, the precise mechanisms of thisactivation are unclear.

Alcohol also is thought to enhance GABAactivity in specific parts of the brain. GABAenhancement has been linked to the reinforcingeffects of alcohol by the observation that drugsthat block GABA activity also decrease alcoholintake in alcohol-preferring rats, while drugs thatincrease GABA activity act as a surrogate foralcohol, maintaining alcohol preference duringalcohol withdrawal (27). In addition, an increasein the number of GABA containing fibers hasbeen observed in the nucleus accumbens ofalcohol-preferring rats as compared with non-preferring rats (34). Part of alcohol’s reinforcingeffects possibly are due to an increase of GABAinhibition on other inhibitory neurons that de-crease the activity of the dopamine neurons in theventral tegmental area. This chain of action wouldhave the ultimate effect of increasing the activityof the dopamine neurons (27). However, the

Chapter &The

Figure 3-4-The GABAA Receptor Complex

Cell membrane

‘-’4Inside the cell

The GABAA receptor complex is made up of a chloride ionchannel surrounded by a GABA receptor (GABA) and abenzodiazepine receptor (BDZ). Activation of the GABAA

receptor complex increases the flow of chloride into a cell,thereby inhibiting the activity of the cell.SOURCE: Office of Technology Assessment, 1993.

experimental evidence supporting this idea isequivocal (27). While it is clear that both GABAand dopamine are involved in the reinforcingaffects of alcohol, the relationship between thesesystems in this action is yet to be defined (27).

Some experimental evidence implicates sero-tonin in the reinforcing effects of alcohol, al-though that involvement is not as clear as fordopamine and GABA. Alcohol-preferring ratsshow a relative deficit in brain serotonin levels ascompared to nonpreferring rats (48) and evidencesuggests that alcoholic patients have lower levelsof serotonin than nonalcoholics (5). In animalstudies, drugs or experimental manipulations thatincrease the levels of serotonin in the brain reducevoluntary intake of alcohol (40). These resultswould seem to indicate that part of the reinforcingeffects of alcohol is due to its inhibitory effect onthe serotonin system. However, a variety ofstudies using animals with experimentally de-pleted serotonin levels has found that this manip-

Neuropharmacology of Drugs of Abuse | 29

ulation decreased alcohol consumption (40). Thus,while serotonin seems to be involved in alcohol’sacute reinforcing effects the exact mechanismsthat may be involved still need to be clarified. Thediscrepancies observed in experiments may ulti-mately be explained by differential effects ofalcohol on serotonin receptor subtypes in variousbrain regions.

In animal studies alcohol self-administration isdecreased by drugs that block the action of theopioid peptide neurotransmitters and is enhancedby drugs that mimic their action, suggesting a rolefor these neurotransmitters in alcohol reinforce-ment (40). However, drugs that block opioidpeptide activity also suppress food and waterintake indicating that their action is not specificfor alcohol but is related to an inhibition ofconsummatory behavior in general (40). Never-theless, as a result of this experimental worknaltrexone, an opioid peptide blocking drug, hasbeen tested in alcohol dependent humans, whereit has been demonstrated to be a promisingadjunct to behavioral relapse prevention treat-ment (50,59).

Chronic administration—Repeated adminis-tration of alcohol results in tolerance to many ofits effects. Tolerance to the motor, sedative,antianxiety, and anesthetic effects of alcohol hasbeen shown in animal studies and tolerance inhumans is indicated by the fact that dependentindividuals increase their consumption over time.How alcohol tolerance develops is not clearlyunderstood, but since alcohol affects the activityin a wide range of neurotransrnitter systems, itmay involve mechanisms common to many or allof them. In particular, an adaptation in membranechannels for the calcium ion following chronicexposure to alcohol may play a significant role inalcohol tolerance (43). Dispositional tolerancealso plays a role.

Alcohol withdrawal in animals is characterizedby CNS hyperexcitability. In humans this hyper-excitability results in anxiety, anorexia, insomnia,tremor, disorientation, and sometimes hallucina-tions. In severe withdrawal a syndrome called


delirium tremens, marked by vivid hallucinations,disorientation with respect to time and place, andoutbursts of irrational behavior, may develop.

In humans, the craving for alcohol duringperiods of abstinence has often been considered aprime factor underlying excessive alcohol use.However, there is no evidence of a correlationbetween development of physical dependenceand a specific craving for alcohol in experimental

.animals (52). This same result has been noted inhuman alcoholics in an experimental laboratorysituation (44). While avoidance of withdrawalsymptoms plays a role in continued alcohol use inhumans, the relationship between the develop-ment of the withdrawal syndrome and alcoholcraving during abstinence needs to be clarified(52).

The CNS hyperexcitability associated withalcohol withdrawal is thought to be related toalcohol-induced alterations in the sensitivity ofGABA and glutamate receptors (40,43). Experi-mental evidence indicates that prolonged alcoholexposure decreases the sensitivity of GABAreceptors (47) and increases the sensitivity ofglutamate receptors (24). With the cessation ofalcohol intake, these changes are manifestedthroughout the brain as a decrease in the overallactivity of the inhibitory neurotransmitter GABAand an increase in the activity of the excitatoryamino acid neurotransmitter glutamate.

BARBITURATESBarbiturates are a class of drugs that depress

CNS activity. First introduced in the early 1900s,barbiturates were widely prescribed as antianxi-ety agents and sleep aids, and to treat otherpsychiatric conditions. However, their lethal over-dose potential and high abuse potential, coupledwith the advent of the safer benzodiazepinecompounds curtailed their use starting in the1960s (46).

Barbiturates’ sedative effects result from theirability to increase GABA activity (54). Theirmechanism of action is through an augmentationof the activity of one of the receptor subtypes for

GABA, the GABAAreceptor (see figure 3-4). TheG A B AA receptor is linked to a chloride ionchannel. Stimulation of the receptor by GABAopens the channel and increases the flow ofchloride into the neuron, which acts to inhibit thecell’s activity. Barbiturates increase the amountof time the chloride channel stays open thusincreasing the inhibitory effects of GABA.

Acute administration—The reinforcing prop-erties of barbiturates have been clearly demon-strated in both animal and human studies (46).

.Animals readily self-administer barbiturates in avariety of different experimental paradigms. Inhumans, studies using self-report measures havedemonstrated that drug-experienced subjects, blindto the identity of the drug, consistently givebarbiturates high rankings when asked to rate aseries of drugs as to ‘liking” or ‘would you takethis drug again?” Also, in controlled studies,human subjects will work to receive barbituratesand will do more work to receive the drug if theavailable dosage is increased (46). The mecha-nism of barbiturate reward is unclear. Since oneof its major effects is to enhance GABA activity,barbiturates, like alcohol, may increase GABAinhibition of other inhibitory neurons that de-crease the activity of the dopamine neurons in theventral tegmental area. Further studies are neces-sary to confirm this possibility.

Chronic administration—With continued usesome tolerance develops to most effects of thebarbiturates (46). Little tolerance develops to thelethal dose. Unlike most other drugs of abuse,both dispositional and phaxmacodynamic toler-ance are important in the development of barbitu-rate tolerance. Barbiturate withdrawal is markedby a severe and sometimes life-threatening with-drawal syndrome (46). Both anxiety and depres-sion are common features, and with heavy,prolonged use, the development of severe grandmal tonic epileptic seizures can occur. Theneurochemical changes responsible for the phar-macodynamic tolerance and withdrawal syn-drome have yet to be clearly established. Someexperimental evidence suggests that tolerance is

Chapter &The Neuropharmacology of Drugs of Abuse | 31

the result of the GABAA receptors becoming lesssensitive to the effects of barbiturates (54). Withdrug cessation, the barbiturate stimulation ofGABA activity ceases and the action of thedesensitized receptors manifests itself as anoverall decrease in GABA activity, resulting inwithdrawal symptoms. Again, the hyperexcitabil-ity that results is similar to what occurs in alcoholwithdrawal.

BENZODIAZEPINESBenzodiazepines are a class of drugs intro-

duced in the 1960s as antianxiety agents (25).They rapidly replaced barbiturates, which havesignificant abuse potential, to treat anxiety andother psychiatric conditions, Like barbiturates,benzodiazepines have a general inhibitory effectin the brain by enhancing GABA activity. Butunlike barbiturates’ nonspecific effect on chlorideion channels, benzodiazepines act by binding toa specific benzodiazepine receptor (21,54). Thepresence of a benzodiazepine receptor in the brainindicates the presence of a naturally occurringendogenous neurotransmitter that normally inter-acts with the receptor. An endogenous benzodiazepine-like neurotransmitter has yet to be identified.

The benzodiazepine receptor is coupled withthe GABAA receptor (figure 3-4). Stimulation ofthe benzodiazepine receptor increases the fre-quency of chloride ion channel opening in re-sponse to GABA binding to the GABAA receptor(21). Also, benzodiazepines enhance the bindingof GABA to its receptor and the presence ofGABA enhances benzodiazepine binding. Thenet affect of benzodiazepines is to augmentGABA activity at the GABAA receptor andenhance GABA action, The antianxiety and othersedative effects of the benzodiazepines are due tothis action.

Acute administration—Most benzodiazepi-nes support only modest levels of self-administration, much below the levels observedwith barbiturates, when given intravenously inanimal studies (25,46). When given orally, benzo-diazepines do not induce self-administration in

animal studies (46). In humans, self-report stud-ies, similar to those used to examine barbiturates,have demonstrated that benzodiazepines yieldmodest rankings of liking and that given a choice,subjects consistently prefer barbiturates overbenzodiazepines (25,46), Since benzodiazepinesact selectively on GABA activity it is probablethat their mild reinforcing properties are due toactivation of GABA mechanisms similar to thosedescribed for alcohol.

Chronic administration—Prolonged expo-sure to benzodiazepines results in tolerance totheir therapeutic and other effects (19,21). Thistolerance maybe due to a reduction in thefunctional activity of GABA as a result of adesensitization of the benzodiazepine receptorcaused by prolonged exposure to the drug (2 1). Aswith alcohol and barbiturates, a withdrawal syn-drome occurs following benzodiazepine drugcessation due to a decrease in GABA activity. Ingeneral, the characteristics of benzodiazepinewithdrawal are similar to barbiturate withdrawal,but at typical benzodiazepine therapeutic dosesthe magnitude of the symptoms are less severethan seen in barbiturate withdrawal. Nonetheless,since benzodiazepines are widely prescribed,their ability to induce physical dependence attherapeutic doses indicates that care must begiven in their administration (25).

| OpiatesThe poppy plant, Papaver somniferum, is the

source of naturally occurring opium. This naturalsubstance contains more than 20 alkaloid com-pounds, including the drugs commonly known asmorphine and codeine. Illicit drugs such as heroinand other semisynthetic opiates are derived byaltering morphine (20). Opiates are drugs, naturalor synthetic, which have opium- or morphine-likeactivity. These drugs, when administered into thebody, mimic the body’s endogenous, or self-produced, opioid peptide neurotransmitters (en-dorphins, enkephalins, and dynorphins). Theopioid peptide neurotransmitters are involved in


three major functions: modulation of pain percep-tion and response to painful stimuli; reward; andregulation of homeostatic functions such as food,water, and temperature regulation (39). Themain types of opioid receptors have been identi-fied in the brain— mu, delta, and kappa (18), allof which are linked to second messengers in thecell (14). In general, the opioid peptide neuro-transmitters have an inhibitory effect on theactivation of neurons (18). Since morphine isselective for the mu receptor, it is thought that theactivation of this receptor is responsible for thereinforcing characteristics of opiates (18,39,40,41).The overall acute and chronic effects of opiatedrugs in the brain involve many interactive brainsystems (39). Related to the function of en-dogenous opioid neurotransmitters, opiate drugsproduce a profound sense of euphoria and well-being coupled with sedation, relaxation, andincrease in pain threshold in humans.

Acute administration-Opiates have an imm-ediate reinforcing effect and are readily self-administered by humans and animals in experi-mental situations (40). The weight of experimen-tal evidence favors a role for dopamine in therewarding effects of opiates, while other systemsmay also be involved (18). Animal studies haveshown that opiates increase the activity of dopam-ine neurons in the ventral tegmental area (18,39,40,41). This increase is via an indirect mechanism(18). Within the ventral tegmental area neuronscontain the inhibitory neurotransrnitter GABA.Those GABA containing neurons have mu recep-tors on them and form synapses with the dopam-ine neurons. Since opioids also inhibit neuralactivity, when the mu receptors are activated byopiates, the GABA receptors release less GABA,which decreases the inhibition on the dopaminecells, causing the dopamine neurons to becomemore active. The net effect of this disinhibition isto increase activity in the ventral tegmentalneurons, which release doparnine in the nucleusaccumbens. This increase in dopamine activityresults in the rewarding and motor stimulatingproperties of opiate drugs. In addition to the

dopamine-dependent mechanism of opiate rein-forcement, there appears to be another componentnot involving dopamine (40,41). This secondcomponent is thought to involve opiate activityon the neurons of the nucleus accumbens and theirconnections to other areas in the front of the ‘brain(41).

Chronic administration—In general, repeatedadministration of opiates results in the develop-ment of marked tolerance to their effects includ-ing their reinforcing effects (15,18). While theprecise mechanism of opiate tolerance is unclear,one hypothesis is that chronic exposure causes adesensitivity of opioid receptors (15,58). Re-peated activation of the receptors by the drugcauses an uncoupling of the receptor from theinternal cellular mechanisms that are activatedwhen the receptors are stimulated normally (58).Experimental evidence also suggests that chronicexposure to opiate drugs may decrease the levelsof endogenous opioid neurotransmitters, contrib-uting to the development of tolerance (58). Thedecrease is believed to be due to an overactivation by the opiate drugs of mechanisms thatnormally regulate the levels of neurotransmitter(58).

Craving and withdrawal are two prominentcharacteristics of chronic opiate administration.In humans withdrawal is characterized by depres-sion, irritability, insomnia, nausea, and weakness(18,36). Chronic morphine administration, likechronic cocaine administration, has been shownto produce changes in the expression of genesinvolved in a number of intracellular mechanismswithin neurons in the ventral tegmental area andnucleus accumbens (10). These changes maycontribute to the craving and feelings of dysphoriaassociated with withdrawal.

The locus ceruleus, a nucleus in the brainstem,has been implicated in the physical signs of opiatewithdrawal (15,39,40). The locus ceruleus iscomposed mainly of neurons containing noradre-naline. These neurons send fibers to numerousbrain structures including the cortex, hippocam-pus, and other structures in the front of the brain


and receive fibers from various structures, includ-ing a strong excitatory input from other areas inthe brainstem, The activity of locus ceruleusneurons is inhibited by opioid neurotransrnittersvia activation of mu receptors (15). Animalstudies have shown that direct electrical stimulat-ion of these neurons produces symptoms similarto those seen in opiate withdrawal (15). Locusceruleus neurons become tolerant to the effects ofopiates after chronic exposure (15,39). An in-creased stimulation of the neurons in the locusceruleus via their brainstem excitatory inputs isthought to occur during opiate withdrawal, result-ing in the enhanced noradrenaline release at themany brain sites that receive inputs from the locusceruleus (15).

| CannabisThe different types of drugs made from Canna-

bis sativa are distinguished by the plant parts usedin preparing the drug. Marijuana consists mainlyof dried plant material such as cut leaves, stems,seeds, and the flowering tops of the plants.Hashish is the dried resin made from the flowertops and sinsemilla is a variety of marijuanaselected for its particularly potent effects andharvested before seed formation. Cannabis ismost frequently smoked, resulting in the rapiddelivery of the drug into the bloodstream, suchthat effects may be felt within minutes and last for2 t0 3 hours. Cannabis may also be administeredorally. However, the plasma concentration islower and takes about an hour to peak.

Cannabis sativa contains psychoactive can-nabinoids. The primary psychoactive componentof Cannabis sativa is the cannabinoid delta-9-tetrahydrocannabinol (THC). Most of the othercannabinoids are either inactive or weakly active.In addition, smoking marijuana produces hun-dreds of other compounds (2). While mostresearch has concentrated on evaluating themolecular and biochemical mechanisms of THCthat underlie the actions of the cannabinoids,these other compounds can also play a role in the

acute and long-term consequences of marijuanause (2).

It has only been in the last few years that aspecific receptor for THC has been identified inthe brain (16,30). This receptor is linked to asecond messenger (14) and is localized to specificbrain regions including the hippocampus, cere-bral cortex, cerebellum, and the axon terminals offibers that arise in the basal ganglia (a brainstructure in the front of the brain involved withmovement) and terminate in the globus pallidus (astructure in the front of the brain involved inmovement and closely connected with the basalganglia) and substantial nigra (located in themidbrain, next to the ventral tegmental area, itcontains dopamine neurons that send fibers to thebasal ganglia) (29,30). The characteristic cogni-tive (e.g., memory impairment) and motor (e.g.,decreased motor coordination) effects of THC arethought to be the result of its action on thesereceptors (29). As with benzodiazepines, theidentification of a specific receptor for THCsuggests that there may be a naturally occurringendogenous neurotransmitter in the brain thatnormally interacts with the receptor. While notpositively identified, several candidates havebeen proposed, including the chemical anan-damide (16).

Since smoking marijuana results in the inhala-tion of many potentially psychoactive com-pounds in addition to THC, the subjective effectsof marijuana vary somewhat among individuals(2). The behavioral response to marijuana mayvary as a function of dose, setting, experience, andexpectation of the user, the cannabinoid contentof the sample, and the compounds that areproduced as the marijuana is burned. Neverthe-less, several behavioral effects are generallyascribed to marijuana use (32). The most promi-nent feature is an initial period of euphoria. Theeuphoria is often followed by a period of drowsi-ness and sedation. Perception of time is alteredand there is a dissociation of ideas, and distortionsin hearing and vision. Some studies have docu-mented impairment on a variety of cognitive and


performance tasks involving memory, percep-tion, reaction time, learning, and motor coordina-tion (2). An amotivational syndrome, character-ized by apathy, dullness and impairment ofjudgment, concentration and memory, along withloss of interest in pursuit of conventional goals,has been described in the literature, and evidenceshows that this syndrome is a result of chronicintoxication (35).

Acute administration-While marijuana pro-duces a feeling of euphoria in humans, in general,animals will not self-administer THC in con-trolled studies (29). Also, cannabinoids generallydo not lower the threshold of the amount ofelectrical stimulation needed to get animals toself-stimulate the brain reward system, as do otherdrugs of abuse; although one series of studies hasshown that in the inbred lewis rat, THC not onlylowers the threshold for electrical self-stimulationbut also enhances the release of dopamine in thenucleus accumbens (22). The enhancement ofdopamine release was blocked by drugs that blockendogenous opioid activity (22) indicating thatendogenous opioids can regulate this response.The fact that these results have been observed inan inbred strain of rat indicates that they havesome inherited variation related to the mechanismof THC. Since THC receptors are not directlyassociated with dopamine neurons (29) and thedopamine response that has been observed ismodulated by opioids, it is likely that the effectsof cannabinoids on dopamine circuits involved inreward are indirect and different from those ofdrugs, such as cocaine and morphine that directlyaffect dopamine levels and produce craving anddrug-seeking behavior (29). Nonetheless, theobservation that the ability of animals to recog-nize the intoxicating effects of THC can bemimicked by drugs that selectively activate theTHC receptor indicates that these effects aremediated through the THC receptor (9,23).

Chronic administration—Tolerance readilydevelops to the behavioral and pharmacologicaleffects of THC in both humans and animalexperimental models (2,5 1). In humans, tolerance

develops to the mood, memory, motor, andperformance effects of the drug (51). The mecha-nism of this tolerance is thought to be a desensiti-zation of the THC receptor, perhaps by somealterations in its interaction with the secondmessenger (2,51).

Cessation of cannabinoid administration doesnot give rise to an intense withdrawal syndrome(2,51). Only a few animal studies show that anywithdrawal symptoms result. Changes that havebeen observed include increased motor and groom-ing activity in rats, altered susceptibility toconvulsion induced by electric shock in mice, andincreased aggressiveness in monkeys (51). Inhumans, withdrawal signs are relatively mild(2,51) and consist of changes in mood and sleep,increased imitability and restlessness, anorexia,and mild nausea. As with all drugs the relativeintensity of the withdrawal syndrome is depend-ent on the quantity, frequency, and duration ofdrug use. While a severe physical dependencephenomenon is not associated with cannabiswithdrawal, the probability of developing a formof craving is high (2). The mechanism for thesevarious withdrawal effects is unknown, but it islikely related to the unmasking of the desensitizedreceptors on drug cessation. Also, both thetolerance and withdrawal phenomena may berelated to alterations in the as yet unidentifiedendogenous neurotransmitter that interacts withthe THC receptor (5 1).

| Lysergic Acid DiethylamideLysergic acid diethyklamide (LSD) is one of a

broadly defined class of drugs known as psyche-delics. Other psychedelics include mescaline andpsilocybin. The effects of the psychedelics aresimilar, but LSD is the most potent (13). Thesedrugs distort the perception of space and time, andproduce exaggerated sensory phenomena in vi-sion, hearing, and touch. The subjective effectsassociated with psychedelic use are stronglydetermined by a number of factors such as setting,expectations, user’s personality, and dose. In


some cases, adverse psychiatric effects occurincluding ‘bad trips’, panic reactions, and evenpsychotic episode during intoxication. Whilethese drugs are some of the most powerfulpsychoactive drugs known and can have adverseconsequences, their dependence potential, asmeasured by their reinforcing properties andneuroadaptive response, is low as compared withthe other drugs discussed in this report. Psyche-delic use has undergone cycles of popularity, suchas during the 1960s, and serves as an example ofhow extrinsic societal factors can affect drug use,in addition to the intrinsic pharmacological ac-tions of a drug.

Acute administration—LSD’s psychedelicproperties are a result of its actions on theserotonin neurotransmitter system (1 1,26). LSDis thought to stimulate the various receptorsubtypes for serotonin, and has particular potencyin activating the serotonin autoreceptor (3). Asimilar activation of the serotonin system is seenwith MDMA, which is a derivative of ampheta-mine and has both dopamine and serotoninstimulating properties. Unlike LSD, MDMAstimulates serotonin neurotransmission by block-ing its reuptake into the presynaptic terminal (l).This action on serotonin gives MDMA psyche-delic properties in addition to its amphetamine-like stimulating properties. To date, no evidenceconfirms that LSD supports self-administration inanimal studies (13).

Chronic administration—Tolerance devel-ops rapidly to LSD and other psychedelics whenthey are repeatedly administered and the extent ofthe tolerance is greater than what is observed withother drugs such as PCP or alcohol (13). Themechanism of LSD tolerance is unclear. SinceLSD stimulates serotonin receptors and a typicalresponse of receptors to continued activation is adesensitization process, it is possible that sero-tonin receptor desensitization plays a role.

Currently, there is no evidence that a with-drawal syndrome is associated with terminationof chronic hallucinogen use (13). The phenome-

non of flashbacks, in which the perceptual changesassociated with LSD spontaneously appear afterdrug cessation, are reported to occur in about 23percent of regular users (31). It unclear whetherflashbacks represent a withdrawal syndrome andare related to, or predictive of, hallucinogendependence (13).

SUMMARYStudies of the pharmacological actions of drugs

of abuse indicate that their reinforcing propertiesmay be due to actions on a common neural circuit.While the mechanisms involved for all drugs ofabuse have not been completely described, many,either directly or indirectly, activate MCLP. Suchdrugs include cocaine, amphetamines, opiates,sedatives, and nicotine. For other drugs of abusethe precise relationship, if any, to the brain rewardsystem is unclear.

Repeated administration of all drugs of abuseis associated with neuroadaptive responses. Ingeneral, tolerance develops to at least some oftheir effects although the specific details of thebiological mechanisms underlying these changesare not completely understood. In terms ofpromoting substance abuse, an important action isthe development of tolerance to the reinforcingproperties of a drug. Available evidence suggeststhat tolerance develops to the reinforcing proper-ties of cocaine, alcohol, PCP, and opiates. Awithdrawal syndrome is associated with mostdrugs of abuse, though the severity varies. Barbi-turates, alcohol, stimulants, opiates, and benzodi-azepines produce pronounced and sometimessevere withdrawal symptoms, while those fornicotine and caffeine is less intense. A mildwithdrawal is associated with cannabis use; whilethere is no evidence of a withdrawal syndromerelated to LSD. Certain aspects of withdrawal,such as changes in mood and motivation, inducedby the chronic drug state may be key factors torelapse and drug-seeking behavior.


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_-—

Genetics 4

w hy does one person become dependent on drugs whileanother, exposed to the same environment andexperiences, does not? As progress in understandingthe role of genetics in various conditions and diseases

increases, there has been a realization that there is likely to be agenetic component to substance abuse and addiction. That is,inherited differences among individuals affect their response todrugs. To date, much of the work done in this field is related toalcoholism, less is known about the genetics of other drugs ofabuse.

Studies in both humans and animals contribute to theunderstanding of genetic factors in substance abuse and depend-ence. Human studies shed light on the question of whether drugdependency is transmitted between generations. In addition, thestudy of individuals with substance abuse problems as well asanimal studies provide information about what is actuallyinherited. For example, are there genetic differences in sensitiv-ity and responsiveness to drugs? And, if yes, are the differencesdrug-specific, or are they related to general mechanisms associ-ated with the actions of all abused drugs? Finally, the tools ofmodern molecular biology can be used to identify the specificgenes that control various cellular and biochemical functionspossibly involved in an inherited component of substance abuseand addiction.

While the existence of inherited differences seems likely, agenetic component alone probably is insufficient to precipitatesubstance abuse and addiction. Unlike disorders such as Hunt-ington’s disease and cystic fibrosis, which result from thepresence of alterations in a single gene, substance abuse is likely

39


to involve multiple genes that control variousaspects of the biological response to drugs. Inaddition, the complex nature of drug dependency,involving many behavioral and environmentalfactors, indicates that any genetic component actsin consort with other nongenetic risk factors tocontribute to the development of substance abuseand addiction. Thus, neither the presence norabsence of a genetic factor ensures developmentof, or protection from, drug addiction.

DO INHERITED FACTORS EXIST?A number of confounding factors complicates

the study of genetic transmission of substanceabuse liability in humans. One is the highincidence of psychiatric conditions among sub-stance abusers (104), which raises questionsabout the role of psychiatric comorbidity inliability to illicit drug addiction. In particular,antisocial personality disorder (ASPD) is oftenassociated with substance abuse. One studyshows that 84 percent of individuals with ASPDalso have some form of substance abuse duringtheir lifetimes (104). Other psychiatric conditionsthat may be associated with substance abuse aredepression, anxiety disorders, manic-depression,and schizophrenia.

Another issue related to studies of the geneticsof liability to abuse of specific drugs is that manydrug abusers engage in multiple drug use, so exam-ining any familial trends in the use of a particulardrug becomes difficult. Finally, rates of illicitdrug use show strong secular trends. Even assum-ing a vulnerability to drug-specific addictions,there might be tremendous variations in expres-sion of addiction, simply because of differencesin drug availability over time: No matter how vul-nerable an individual might be, addiction requiresexposure. Such issues often hamper studies on thegenetic transmission of drug liability.

I Family Studies

ALCOHOLISMReferences to a familial tendency or hereditary

‘‘taint’ of alcoholism date back to classical times(44); an observation repeatedly confirmed byfamily studies. While not all cases axe familial,the risk of alcoholism consistently has been foundto be higher among frost-degree relatives (i.e.,parents, siblings, children) of alcoholics as com-pared to the general population (79). Moreover,while family studies can establish that a disorder(or liability to a disorder) is transmitted; ingeneral, they are unable to distinguish betweenbiological and cultural transmission (though thisissue can be evaluated in large family studies byanalyzing multiple classes of relatives with differ-ing degrees of genetic relatedness).

Results of numerous family studies indicatethat alcoholism segregates within families, withmale first-degree relatives of alcoholics having ahigher incidence (ranging from 27 to 54 percent)than female first-degree relatives (6 to 17 percent)as compared to first-degree relatives of nonalco-holics (20 percent of males, 4 percent of females)(49,103,133). In fitting models of inheritance tofamily data, researchers concluded that observedpatterns of inheritance were consistent with thehypothesis that familial factors predisposing toalcoholism were the same in men and women, butthat nonfamilial environmental factors exertedmore influence in the development of alcoholismin women (20). Familial alcoholics (those with atleast one relative with alcoholism) appear to haveearlier onset, more antisocial symptoms, moresocial complications of alcohol use, and worsetreatment outcome than nonfamilial alcoholics(38,93,111).

Familial is not identical to genetic, and in thecase of alcoholism, the familial patterns ofinheritance are not consistent with those of apurely genetic condition (58,109). In addition,evidence suggests that the transmissibility ofalcoholism has increased over time (102). Thus,any genetic factors promoting the development of

Chapter 4-Genetics | 41

alcoholism are significantlygenetic influences.

OTHER DRUGS

moderated by non-

Fewer family studies have been conducted onthe genetic transmission of liability to other drugsof abuse. Nonetheless, the evidence availablesuggests that, as in the case of alcohol, addictionto other psychoactive substances appears to run infamilies.

One study found evidence for familial aggrega-tion of drug use, based on family history obtainedfrom individuals admitted for substance abusetreatment (78). However, this study also com-bined use of all illicit drugs into one category andrelied on self-reports by the subject on his or herdrug use as well as that of family members. In alarge family interview study comparing 201opiate addicts and 82 normal controls, as well asinterviews of 1,398 first-degree relatives of these

‘subjects, the relatives of opiate users had elevatedrates of drug addiction as compared with thecontrols (105). In addition there was an associa-tion between opiate use and the presence ofASPD. Further analysis of these data revealedthat the incidence of both drug abuse and ASPDwas higher among the siblings of the opiatesubjects than among their parents (69,70).

Some studies note a familial association be-tween opiate addiction and alcoholism (65).However, another family history study (51),comparing families of 32 alcoholics, 72 opiateaddicts, and 42 individuals addicted to bothsubstances, found that while both opiate addictionand alcoholism clustered within families, co-occurrence of the disorders within families oc-curred no more frequently than expected bychance, thus supporting the hypothesis of inde-pendent transmission. However, a later study of201 opioid addicts and 877 of their first-degreerelatives also showed familial aggregation of bothalcoholism and depressive illness suggesting apossible co-occurence of the disorders (64).

Little research has been done to test hypothesesregarding familial transmission of liability toaddiction to specific substances other than opiatesor alcohol. One study involving 350 treated drugabusers and 1,478 relatives, found that alcoholismwas equally common among relatives of individ-uals who preferentially abused opiates, cocaine,or sedative-hypnotics (27 percent, 31 percent, and24 percent of male relatives, respectively), whereasrelatives of sedative-hypnotic users were subjectto diagnoses of other substance abuses (2 percentof male relatives, versus 11 percent of malerelatives of opiate abusers and 16 percent of malerelatives of cocaine abusers) (80).

I Twin and Adoption StudiesWhile family studies can establish that a

disorder (or liability to a disorder) runs in afamily, they generally are unable to distinguishbetween biological and cultural transmission.However, two other methods are used to helpdisentangle the effects of genetic and nongeneticfactors. Adoption studies compare the presence ofa trait among biological versus adoptive familymembers or other control groups. In this wayindividuals that share the same environment butdifferent genetic heritages, or vice versa, can becompared. Twin studies, by contrast, involvesiblings raised in the same environment, butcompare how often identical twins, who aregenetically identical, and fraternal twins,1 whoare not, are similar, or concordant, for a trait. Ahigh concordance rate for a trait among identicaltwins versus fraternal twins usually indicates agenetic component for the trait.

TWIN STUDIESEvidence fromn twin studies suggests genetic

influences on ‘ drinking patterns as well as alcohol-related problems. Results from twin studiesdemonstrate genetic influences on measures ofalcohol consumption such as abstention, average

1 Fraternal twins share the same in utero environment but are genetically no more similar than any two siblings,


alcohol intake, and heavy alcohol use (50,60,92).Twin studies also indicate an inherited risk forsmoking (24).

When evaluating how alcoholism develops,twin studies generally support the existence ofgenetic influences on the development of thedisorder. One study found a higher concordancerate for alcohol abuse between identical twins (54percent) versus fraternal twins (28 percent) (57),while two subsequent studies found no suchrelationship (48,92,). A 1991 study (94) examined50 male and 31 female identical twin pairs and 64male and 24 female fraternal twin pairs, with 1member of the pair meeting alcohol abuse ordependence criteria. The study found that identi-cal male twins differed fromn fraternal male twinsin the frequencies of both alcohol abuse anddependence as well as other substance abuseand/or dependence. On the other hand, femaleidentical and fraternal twins were equally likely toabuse alcohol and/or become dependent on othersubstances, but identical female twins were morelikely to become alcohol dependent. Anotherstudy of 356 twin pairs also found higher identicalthan fraternal rates of concordance for problemsrelated to alcohol and drug use as well as conductdisorder (77). The same study also noted thatamong men, heritability was greater for earlyrather than late onset of alcohol problems, whereasno such effect was seen for women. Finally, astudy of 1,030 female twin pairs found evidencefor substantial heritability of liability to alcohol-ism, ranging from 50 to 60 percent (61).

Thus, twin studies provide general agreementthat genetic factors influences certain aspects of

. .drinking. Most twin studies also show geneticinfluence over pathological “drinking, includingthe diagnosis of alcoholism, which appears (likemany psychiatric disorders) to be moderatelyheritable. Whether genetic factors operate compa-rably in men and women, and whether severity ofalcoholism influences twin concordance is lessclear. How psychiatric comorbidity may affectheritability of alcoholism also remains to bestudied.

ADOPTION STUDIESAdoption studies have supported the role of

heritable factors in risk for alcoholism (1 1,18,1 17).The results from a series of studies conducted inDenmark during the 1970s are typical. Of 5,483nonfamily adoption cases from the copenhagenarea between 1924 and 1947, the researchersstudied 55 male adoptees, and later compared 20adoptees with 30 nonadopted brothers. They alsostudied 49 female adoptees, comparing them with81 nonadopted daughters of alcoholics. Compari-sons also were made with matched controladoptees. The Copenhagen study revealed thatadopted-away sons of alcoholic parents were fourtimes as likely as adopted-away sons of nonalco-holics to have developed alcoholism; evidencealso suggested that the alcoholism in these caseswas more severe. The groups differed little onother variables, including prevalence of otherpsychiatric illness or “heavy drinking.” Beingraised by an alcoholic biological parent did notfurther increase the likelihood of developingalcoholism. That is, rates of alcoholism did notdiffer between the adopted-away children andtheir nonadopted brothers. In contrast, daughtersof alcoholics were not at elevated risk of alcohol-ism. Among adoptees, 2 percent had alcoholism(and another 2 percent serious drinking prob-lems), compared with 4 percent of alcoholismamong the adopted controls and 3 percent amongnonadopted daughters (44).

Another analysis examined factors promotingdrug abuse as well as alcoholism (17). In thisstudy, all classes of illicit drug use were collapsedinto a single category of ‘‘drug abuse. ” Most ofthe 40 adopted drug abusers examined hadcoexisting ASPD and alcoholism; the presence ofASPD correlated highly with drug abuse. Amongthose without ASPD, a biological background ofalcoholism (i.e., alcoholism in a biological par-ent) was associated with drug abuse. Also,turmoil in the adoptive family (divorce or psychi-atric disturbance) was also associated with in-creased odds for drug abuse in the adoptee.

Chapter 4-Genetics |43

Finally, results from other adoption studiessuggest two possible forms of alcohol abuse(12,19). The two forms have been classified as“milieu-limited” or type 1 alcohol abuse and“male-limited” or type 2 alcohol abuse (21).Type 1 alcohol abuse characterized by mildalcohol problems and minimal criminal behaviorin the parents, is generally mild, but occasionallysevere, depending on presence of a provocativeenvironment. Type 2 is associated with severealcohol abuse and criminality in the biologicalfathers. In the adoptees, it was associated withrecurrent problems and appeared to be unaffectedby postnatal environment.

I n summary, adoption studies of alcoholismclearly indicate the role of biological, presumablygenetic, factors in the genesis of alcoholism. Theydo not exclude, however, a possible role fornongenetic, environmental factors as well. More-over, evidence suggests more than one kind ofbiological background conducive to alcoholism.In particular, one pattern of inheritance suggestsa relationship between parental antisocial behav-ior and alcoholism in the next generation. Thus,

adoption studies, like othereven at the genetic level,homogeneous construct.

designs, suggest thatalcoholism is not a

WHAT IS INHERITED?Although studies indicate that genetics contrib-

utes to alcoholism and probably other drug abuse,they lack information about what exactly isinherited. For example, do individuals with afamily history of drug abuse have an increasedsusceptibility or sensitivity to the effects of drugswith reinforcing properties? If a susceptibilityexists, what are the biological mechanisms thatunderlie it? To understand what might be inher-ited, both individuals who have a substance abuseproblem and animals models of substance abuseare studied. Various types of information can bederived from these studies. As with family, twin,and adoption studies, much more information is

available about alcoholism as compared withother drugs of abuse.

First, specific inherited risk markers for alco-holism and other substance abuse can be identi-fied. A risk marker is a biological trait orcharacteristic that is associated with a givencondition. Thus, if an individual is found to havean identified marker for substance abuse, he orshe is at risk for developing a drug dependency.To date, no biological characteristic has beenclearly identified as being a risk marker for eitheralcoholism or substance abuse, although evidencesuggests some possible candidates. The identif-cation of a valid and reliable risk marker couldprovide important information about the funda-mental mechanisms underlying substance abuseand addiction and would be an invaluable aid indiagnosis and treatment.

Second, inherited differences in biochemical,physiological, and anatomical processes relatedto differences in drug responses might be identi-fied and studied. Thorough biological assays canbe performed using animal models of substanceabuse. Animal models of substance abuse consistof strains of animals (usually rodents) that havebeen selectively bred to either exhibit a prefer-ence for taking a drug, exhibit a preference for nottaking a drug, or differ in some way in theirbehavioral or physiological response to a drug.Thus, such differences represent inherited traitsrelated to drug-taking behavior, and these animalscan be studied to determine what biologicalmechanisms are involved in the expression ofsuch traits.

Finally, the genetic technique of linkage analy-sis can narrow the area on a chromosome wherea gene may be located. It can lead to theidentification of the gene itself, which, in turn,can improve the understanding of the molecularevents that underlie the expression of the gene.There have been few genetic linkage studiesrelated to substance abuse since few specificbiological traits associated with drug dependencyhave been identified. Some studies in humanshave been carried out related to alcoholism but the


findings of these studies are contradictory andinconclusive (see later discussion).

Specific Risk Markers

ELECTROPHYSIOLOGICAL ACTIVITYAttempts to correlate distinctive patterns of

spontaneous electrical activity of the brain withalcoholism and substance abuse have been equiv-ocal. A few studies have found distinctive electro-encephalograph (EEG) patterns in individuals atrisk for alcoholism (32,39), but others have not(31,59,101). Similarly, the use of alcohol chal-lenge (i.e., giving the subject alcohol and thenrecording EEG) on subjects at high risk foralcoholism has likewise yielded inconclusiveresults. The rationale for challenge studies restson the observation that alcohol has been shown toaffect resting EEG, and thus might have adifferential effect on those at low and high risk foralcoholism (100). Again, some studies have seendistinctive responses (100,101), while other havenot (39,59).

A logical extension of studying resting EEGactivity is examining event-related potentials(ERPs). ERPs are patterns of brain electricalactivity produced in response to a particularstimulus (e.g., auditory, visual); they can reflecta variety of sensory and cognitive processes.Since ERPs may reflect heritable differences incognitive function or capability that may in turncontribute to liability to alcoholism, some havesuggested that ERP changes may allow discrimin-ation between those at low and high genetic riskfor alcoholism. The results of these studies havealso been equivocal. Some have found character-istic responses among individuals at risk foralcoholism (3,4,33,52,53,89,90,125) while othershave not (95,96,97,98). In addition to beingequivocal, the specificity for alcoholism of suchfindings is unclear. In particular, it is not yetknown whether similar findings might be identi-fied in subjects with (or at risk for) illicit drugabuse.

Currently, both EEGbest viewed as possible

and ERP findings seemmarkers. Further studies

are needed to confirm or refute the positive resultsthat have been observed. In addition, while ERPfindings in particular might relate to aspects ofsensory, perceptual, or cognitive functioning thatmay differ among those at risk for alcoholism,how such differences contribute to risk foralcoholism and perhaps substance abuse is notwell understood.

BIOCHEMICAL ASSAYSSerotonin—Results over the last two decades

from both human and animal studies have sup-ported a relationship between low levels ofcentral nervous system (CNS) (i.e., brain andspinal cord) serotonin and impulsive and violentbehavior (130,131). Since problematic use ofalcohol (as well as other drugs) has long beenassociated with a wide range of violent behavior,scientists have examined the relationship be-tween alcoholism and serotonergic abnormalities.While a consistent relationship between alcohol-ism and low CNS levels of serotonin and itsmetabolizes is lacking, mounting evidence sup-ports the presence of such abnormalities in asubgroup of alcoholics with early-onset problemsand a history of violence (16,67,68,107,130).

Because measures of serotonin activity aredifficult to obtain, researchers have used pharma-cologic probes of serotonin function, such ashormonal response to drugs that affect serotonin.These indirect measures have also indicated arelationship between impulsivity, substance abuse,and abnormal serotonin function (37,42,71,83).

For alcoholism, given that early-onset alcohol-ism and ASPD overlap substantially (16), thespecificity of the serotonin findings is unclear,especially as similar results have been found insubstance abusers with ASPD (71). However, atleast one report has indicated that, even aftercontrolling for the presence or absence of ASPDand illicit drug abuse, other neurochernical fin-dings remained significantly associated with alco-holism (106). While further work might delineate

Chapter 4-Genetics| 45

the relationship between decreased CNS sero-tonin levels and Specific psychiatric syndromes,current evidence suggests relatively specific bio-logical differences may exist between early- andlate-onset alcoholics; raising the possibility ofdefining biologically homogeneous subgroups.

Aldehyde and alcohol dehydrogenase en-zymes-Many Asians rapidly develop a promi-nent facial flush following ingestion of a smallamount of alcohol. Continued drinking leads tonausea, dizziness, palpitations, and faintness.This reaction is due to inactivity in individuals’aldehyde dehydrogenase, an enzyme that helpsmetabolize (i.e., break down) alcohol in the body.Ineffective enzyme activity results in a buildup ofthe chemical acetaldehyde in the blood followingalcohol consumption. Clinicians have taken ad-vantage of the aversive properties of acetaldehydebuildup by using the drug Antabuse to inhibitaldehyde dehydrogenase, thus inducing a severeform of the adverse reaction in abstinent alcohol-ics who begin to drink (30,135).

Alcohol dehydrogenase is another enzymeinvolved in the metabolism of alcohol. A mutantform of alcohol dehydrogenase also produces atransient increase in the acetaldehyde concentra-tion after alcohol ingestion. This form of theenzyme also has been reported in Asian popula-tions.

The two enzymes, aldehyde and alcohol dehy -drogenase, probably interact in some individualsto amplify the adverse reaction to alcohol con-sumption (129). Since this reaction discouragesheavy “drinking, the observation that it commonlyoccurs in some populations where alcoholism isrelatively rare suggests that alcohol and aldehydedehydrogenase mutations might be a major deter-minant of alcohol consumption, abuse, and de-pendence. This would seem to hold true forTaiwan and Japan where the reaction occurs in 30to 50 percent of individuals.

The genetics of the aldehyde and alcoholdehydrogenases are well described. The produc-tion of the different forms of these enzymes iscaused by variations of their normal genes. The

presence of these gene variations in an individualaccounts for variations in the metabolism ofalcohol (54). Thus, the presence of these genescan also effect alcohol consumption. For exam-ple, the gene variations that code for the ineffec-tive form of aldehyde dehydrogenase is not onlyless common in alcoholics, but also is rare inJapanese patients with alcoholic liver disease(27, 121,135). Despite identification of such genes,the relationship between their inheritance and thefamilial transmission of alcoholism remains un-studied.

Alcohol challenge-A number of studies havebeen conducted investigating the effect of admin-istering alcohol to young adult sons of alcoholics(99). These studies indicate that, despite similar-ity of blood alcohol levels, sons of alcoholicsdemonstrate less intense subjective responses toalcohol, as well as less intense upper body sway(110,111,113,114). Thus, one mechanism bywhich alcoholism might develop is that sincethese individuals have less of a reaction toalcohol, they would find it more difilcult toself-regulate alcohol consumption, thus increas-ing the risk of developing dependence. In con-junction with these findings, other studies havefound that sons of alcoholics demonstrate slightlylower levels of certain hormones (i.e., prolactin,cortisol, adrenocorticotropin hormone (ACTH))after ingesting alcohol as compared to controls(82,1 14,115,116,1 18). The relationship, if any, ofthese decreased hormonal levels to alcohol con-sumption is unclear.

COGNITIVE DIFFERENCESStudy of high-risk populations (e.g., sons of

alcoholics) has revealed temperamental, as wellas biological, differences between high-risk andcontrol subjects, leading to the suggestion thatvulnerability to alcoholism can be conceptualizedfrom a behavior-genetic perspective (127). Heri-table, constitutional differences, in other words,might affect temperament and, hence, risk foralcoholism and addiction to other drugs. Inparticular, these differences might influence cog-


nitive styles, learning ability, and capability tocontrol one’s own behavior.

In general, it appears that sons of alcoholicsdemonstrate group differences from low-riskpopulations in that the former tend to haveimpairment on tests of cognitive development,academic achievement, and neuropsychologicalfunction (34,12,8). However, the magnitude ofthese differences may depend greatly on how thepopulation is ascertained. To date, little is knownof what specific psychological, temperamental, orcognitive factors might distinguish between high-risk subjects who actually go on to developalcoholism from those who do not (128).

I Biological Mechanisms.Animals that have been bred for specific

characteristics are a valuable tool in drug use andabuse research. For example, certain strains ofrodents differ in their response to the analgesicand body temperature regulating effects of mor-phine, the motor activating effects of stimulantdrugs, and the convulsant producing properties ofbenzodiazepines (28,122). Since the essentialcharacteristic of human drug abuse and addictionis persistent drug-seeking behavior, the mostsalient models are those of genetic differences indrug self-administration and the factors associ-ated with it (e.g., tolerance). While there are somegenetic models of self-administration or prefer-ence for different drugs (i.e., alcohol, opiates,cocaine) (28,41), more information is availableabout the hereditary biological mechanisms thatunderlie the self-administration of alcohol thanother drugs.

ALCOHOLA general working hypothesis is that alcoholics

are sensitive to the low-dose rewarding propertiesof alcohol, are less sensitive to the high-doseactions of ethanol (i.e., have a higher aversivethreshold) and develop tolerance to the aversiveeffects of alcohol. The fact that rats can beselectively bred to have such alcohol drinking

characteristics supports a genetic link to thesetraits.

Dopamine and alcohol intake-Studies ofdopamine content in the brains of two differentstrains of rats bred for either preference ornonpreference for alcohol have found 25 to 30percent lower levels of dopamine in the nucleusaccumbens and the olfactory tubercle of thealcohol-preferring rats (45,74,86). No other dif-ferences in dopamine content have been observedin other brain areas. These data suggest anabnormality in the dopamine system projectingfrom the ventral tegmental area to limbic regions(nucleus accumbens and/or olfactory tubercle) ofthe alcohol-preferring rats. Since this system isthought to be involved in mediating the actions ofvarious drugs of abuse (see ch. 2) and alcohol isthought to increase dopamine levels in the system(see ch. 3), it may indicate that an abnormalfunctioning of the mesocorticolimbic dopaminesystem might be involved in promoting highalcohol “drinking behavior. That is, the alcoholpreference may be related to the ability of alcoholto compensate for the abnormality. The nature ofthis abnormality is unknown but may be due toone or more of the following factors: decreaseddopamine synthesis, a lower number of dopamineneurofibers, and/or reduced functional activity ofdopamine neurons.

Some evidence exists that the mesocortico-limbic dopamine system may respond to systemicethanol administration to a greater degree in thealcohol-preferring strains than in the nonprefer-ring strains. Studies have found that levels ofdopamine metabolizes were higher in areas of thissystem (i.e., caudate nucleus, medial prefrontalcortex, and olfactory tubercle) after ingestion ofalcohol in alcohol-preferring rats as compared tononpreferring rats (35,36). Also, one study hasreported that the oral self-administration of alco-hol, under experimental conditions where theanimal was allowed to receive alcohol as a rewardfor performing a task, increased the synapticlevels of dopamine significantly more in thenucleus accumbens of these alcohol-preferring

rats than in nonpreferring rats (132). It was alsoestablished that the alcohol-preferring strain ofrats will self-administer alcohol directly into theventral tegmental area (73,74). These studiessuggest that the mesocorticolimbic dopaminesystem is involved in regulating alcohol drinkingbehavior and that alcohol may be a strongerpositive reinforcer in alcohol-preferring rats thanin the nonpreferring rats.

Differences in dop amine receptor populationshave also been reported. Two genetically deter-mined high-alcohol seeking lines of rats havebeen reported to have fewer of one type ofdopamine receptor (i.e., the D2 receptor) in theirlimbic system compared with the nonalcoholicrats (74,124), Twenty percent fewer D2 receptors

were observed in the olfactory tubercle andnucleus accumbens of these rats. These studies,along with genetic linkage studies (see laterdiscussion), provide support for the involvementof the D2 receptor in alcohol-preference.

Serotonin and alcohol intake--Examinationof alcohol-preferring and nonpreferring rats hasindicated a relationship between high alcoholpreference and a deficiency in the CNS serotoninsystem. A number of studies have reported 10 to30 percent lower levels of serotonin and itsmetabolizes in the brains of alcohol-preferringrats as compared with alcohol nonprefening rats(45,66,74,84,85,86). Only one study, using astrain of rats not used in any of the others, did notfind lower brain serotonin levels (63). Areas ofthe brain found to have low serotonin levelsinclude the cerebral cortex, frontal cortex, nu-cleus accumbens, anterior and corpus striatum,septal nuclei, hippocampus, olfactory tubercle,thalamus, and hypothalamus.

Since several of these CNS regions may beinvolved in mediating the rewarding properties ofdrugs of abuse, including alcohol, these findingssuggest a relationship between lower contents ofserotonin in the brain and high alcohol preference.Evidence suggests that the serotonin system isinvolved in regulating the activity of the dopa-mine mesocorticolimbic system ( 136). Also, some

. . . . . . . . -- — .


of the areas found to have low serotonin levels(i.e., hypothalamus, hippocampus) may be in-volved in mediating the aversive effects ofalcohol. Since the development of tolerance to theaversive actions of alcohol is one possible charac-teristic of alcoholic abuse, a deficiency in sero-tonin in these areas may be an innate factorpromoting tolerance to the aversive effects ofethanol in alcohol-preferring lines of rodents.

Further study of one of the rat strains used inthese studies showed that low serotonin in thealcohol-preferring line compared with the non-preferring line was due to fewer serotonin con-taining axons (137). This study found fewerserotonin presynaptic fibers forming synapses inthe nucleus accumbens, frontal cortex, cingulatecortex, and hippocampus of alcohol-preferringrats. These results suggest that the low serotoninis the result of structural differences in the CNSserotonin system rather than lower production ofserotonin. Examination of this same strain of ratsfound that there were increased numbers of onetype of post-synaptic serotonin receptor in areasof the frontal cortex and hippocampus (73,76,134).This increase in the number of serotonin postsyn-aptic receptors may represent a compensation forthe lower number of presynaptic serotonin fibers.No such increase in receptors was found in thestrain of rats with normal levels of brain serotoninactivity discussed earlier (62).

Overall, the animal data favors an inverserelationship between the functioning of the CNSserotonin system and alcohol drinking behavior.Thus, innate low functioning of the serotoninsystem may be associated with high alcoholpreference. In support of this concept, somestudies have found lower cerebrospinal fluidserotonin metabolize concentrations in alcoholicsthan in various control populations (2,14).

GABA and the actions of alcohol—Evidenceindicates that alcohol can exert some of itsantianxiety and intoxicating effects by potenti-ating the actions of the neurotransmitter gammaamino butyric acid (GABA) at the G A B AA

receptor (see ch. 3) and that this receptor might be


involved in mediating alcohol drinking behaviorof alcohol-preferring rats (75). However, little hasbeen published that indicates an innate abnormal-ity may exist in the GABA system that could beassociated with alcohol preference. A recentstudy examined the densities of GABA contain-ing fibers in the nucleus accumbens and otherbrain areas of two different strains of alcohol-preferring and nonprefering rats (55). The resultsof this study indicated a higher density of GABAfibers in the nucleus accumbens of the alcohol-preferring rats compared with the nonpreferringrats. There were no differences between therespective lines in the other regions. These resultssuggest alcohol preference may involve an innate,abnormal GABA system within the nucleusaccumbens.

The experimental drug RO 15-4513 binds tothe GABAA-BDZ-Chloride channel receptor com-plex (see ch. 3) and is known to block the actionsof alcohol at this receptor (126). The administra-tion of RO 15-4513 reduced alcohol but not waterintake in a study using one of the alcohol-preferring line of rats (75). The blocking effect ofRO 15-4513 on alcohol intake could itself beblocked by administration of a drug that blocksthe benzodiazepine receptor. These results indi-cate that the GABAA-BDZ-chloride channel re-ceptor complex may be involved in mediating thereinforcing actions of ethanol that promote alco-hol drinking behavior in these rats. The observa-tion that RO 15-4513 blocks oral self-adminis-tration of alcohol supports this idea (56,108).Furthermore, treatment with a drug that activatesthe GABAA receptor was shown to markedlyincrease the acquisition of voluntary ethanolconsumption in laboratory rats (123). Also,GABAA receptor function is enhanced by alcoholin animals selected for sensitivity to alcoholintoxication, but alcohol has little effect onGABAA receptors of animals selected for resis-tance to alcohol intoxication (28). Overall, theseresults are consistent with the involvement of theGABAA receptor in regulating alcohol consump-tion. (See also ch. 3).

Alcohol withdrawal severity—Animal mod-els have been developed for differential geneticsusceptibility to alcohol withdrawal. For exam-ple, withdrawal seizure-prone mice display ahigher incidence of convulsions than do seizure-resistant mice when exposed to identical alcoholconcentrations (29). Other studies suggest thatthis alcohol withdrawal reaction is mediated byan increased sensitivity of channels for calciumions, coupled to receptors for excitatory aminoacids (46,47). Several results have emerged instudies of these mouse lines that are potentiallyimportant for understanding drug abuse. Forexample, studies indicate that independent ge-netic factors control alcohol sensitivity, toler-ance, and dependence, suggesting that thesefeatures of drug abuse are maintained by differentneurobiological mechanisms (28). In addition, thealcohol withdrawal seizure-prone mice have moresevere withdrawal to other depressant drugs (i.e.,diazepam, phenobarbital, nitrous oxide) (6,7,8)suggesting that a group of genes acts to influencedrug withdrawal severity not only to alcohol, butalso to a number of other depressant drugs.

OTHER DRUGSA variety of strains of rats and mice has been

developed that exhibit genetic variations in theirsensitivity to the reinforcing effects of drugs ofabuse and in their drug-seeking behavior (28). Inaddition, genetic differences in various biologicaland neurochemical mechanisms have been ob-served in these animals.

For example, strains of rats and mice that differin their sensitivity to the reinforcing properties ofcocaine and in their cocaine-seeking behaviorhave also been observed to have differences in thenumber of dopamine containing neurons andreceptors in certain brain areas (120). While therole of these biological findings in the expressionof the behavioral traits is unclear, given thatdopamine is the key neurotransmitter in cocaine’saction, it is likely that a link may exist. Otherstudies have shown that the development ofnicotine tolerance is genetically related. Strains of


mice that differ in the rate at which they developtolerance to nicotine have also been found todiffer in nicotine receptor changes followingchronic administration of the drug (72). Thus,inherited differences in nicotine receptor mecha-nisms may underlie inherited differences in thedevelopment of nicotine tolerance.

A recent study indicates that inherited differ-ences in the intracellular mechanisms of theneurons in the mesocorticolimbic pathway couldcontribute to a genetic predilection to drugaddiction (87). In a comparison of rats with eitherhigh or low rates of self-administering drugs ofabuse, the higher self-administering strain exhib-ited differences in the intracellular mechanismsthat control activity in the neurons of the ventraltegmental area and nucleus accumbens (5).

The further examination of causative relation-ships between inherited neurochemical altera-tions and inherited behavioral traits would pro-duce valuable information about the biologicalmechanism that underlies genetic factors relatedto substance abuse and addiction. The recentdevelopment of new and more sensitive tech-niques to analyze brain activity and processes willfacilitate such studies.

I Linkage StudiesGenetic linkage studies establish an associa-

tion between an area of a specific chromosomeand the expression of a trait. Linkage analysisuses specific markers that identify the area on achromosome that might contain the gene ofinterest. If the marker consistently occurs inassociation with the expressed trait, then it islikely that the gene interest is in chromosomalregion.

In the area of substance abuse and addiction,genetic linkage studies have purported to show alinkage between the gene for the dopamine D2

receptor and alcoholism. The gene for the D2

receptor has two forms associated with twomarkers, the A 1 and A2 alleles. The Al alleleoccurs in about 20 percent of the population,

while the AZ allele is found in the remaining 80percent (l). Two separate studies (9,10) reportedthat the frequency of the Al allele for the D2

dopamin e receptor was significantly greater insevere alcoholics compared with nonalcoholics.Furthermore, another study (88) found that indi-viduals with the Al allele had fewer D2 receptorsthan those with the A2 allele. In agreement withthese findings, another study (91) observed asignificant association between the Al allele ofthe D2 receptor and alcoholism. An association ofthe Al allele with alcoholism and decreasednumbers of D2 dopamin e receptors implies a rolefor an inherited deficit in the dopamine system inalcoholism. However, in contrast to these results,other studies have not found an associationbetween the frequency of the Al allele of the D2

receptor and alcoholism (13,26,40,1 19). The dis-crepancies between these studies has called intoquestion the validity of the association of the Alallele with alcoholism.

Moreover, the report of a higher prevalence ofthe Al allele not only in alcoholics, but also inother disorders such as autism, attention deficithyperactivity disorder, and Tourette’s syndrome(25), suggests that the presence of the Al allele isnot specific for alcoholism, but that it has a morediffuse effect that can contribute to the occurrenceof other conditions. Also, recent findings indicatethat the frequency of the Al allele varies mark-edly among different populations (e.g., it is highin some Native Americans) but there does notappear to be an association with its increasedfrequency and the occurence of alcoholism (43).This complexity, coupled with the heterogeneousand complex nature of alcoholism, could accountfor the disagreements among these studies. Suchcomplexity makes construction of appropriatecontrol groups difficult, which in turn can affectstudy results. Additional research is needed tounravel the disagreement and establish the impor-tance of these findings. It might be that thepresence of the Al allele is not unique toalcoholism, but rather, causes a general alteration


in the brain dopamine system that then exacer-bates or contributes to alcohol abuse.

SUMMARYThe existence of heritable influences on normal

and pathological consumption of alcohol is sup-ported by results from family studies, twinstudies, and adoption studies as well as researchon animal models. Animal studies have estab-lished that alcohol preference and the reinforcingactions of alcohol are influenced by geneticfactors. While there have been fewer studiesexamining the genetic component of vulnerabil-ity to the addictive properties of other drugs ofabuse, evidence from animal studies supports agenetic influence on the use and abuse of drugsother than alcohol. The study of nonalcohol drugabuse in humans is more difficult because ofsubstantially smaller populations that use orabuse these drugs and marked changes in availa-bility and, hence, exposure to these agents.Investigation in this area is further hampered bythe complexity of subjects’ drug use: Most drugabusers have used multiple agents. This has ledresearchers either to concentrate on one class ofdrug or to treat all illicit drug use as equivalent.The tendency to lump all illicit drugs into onecategory makes results difficult to interpret orcompare.

In the case of alcohol, studies indicate that lowdoses of alcohol are stimulating and produce astrong positive reward in animals susceptible tothe addictive properties of alcohol. Anothercomponent of excessive alcohol consumptionmight be that alcoholics have a high threshold tothe aversive effects of ethanol. This could be aresult of an innate low sensitivity to medium andhigh doses of alcohol and/or acute tolerance to itsaversive effects. Results from animal studiessuggest an association between high alcoholpreference and acute tolerance to the medium-andhigh-dose effects of ethanol. These animal exper-iments need to be extended and considerationshould be given to related studies in humans.

Findings with animals selectively bred for alco-hol preference need to be extended to studies ofsensitivity, tolerance, and preference for otherdrugs of abuse.

Neurobiological evidence points to commonpathways mediating the positive reinforcing ac-tions of alcohol and other drugs of abuse. Mostevidence is consistent with the involvement of themesocorticolimbic dopamine system in drug rein-forcement mechanisms. Other neuronal pathwaysthat regulate the activity of the mesocorticolimbicdopamine system may also be involved in mediat-ing the rewarding properties of ethanol and otherdrugs of abuse. In the case of serotonin, innate,genetically determined factors appear to reduceCNS activity of serotonin, which is associatedwith heavy alcohol drinking. In addition, animaland human studies suggest an inherited differencein dopamine response to alcohol consumptionand possibly an anomaly in the D2 receptor forDopamine associated with alcohol abuse. Addi-tional studies with animals and humans areneeded to clarify these differences and to explorethe relationship of other neurobiological mecha-nisms related to the inherited components of otherdrugs of abuse.

Alcoholism and drug abuse are complex condi-tions that are the result of multiple causal factors.Alcoholism and other forms of addiction repre-sent entities that have a genetic component butrequire specific (but as yet poorly understood)environmental influences to manifest. Thus, con-sideration of the impact of genetic factors mustalso take into account general social conditionssuch as availability and cost of substances,acceptability of use, and specific environmentalinfluences on initiation of use, maintenance orcessation of use, and development of use-relatedproblems. A major goal of addiction research inclinical populations is to determine who isvulnerable under what conditions. Understandingthis interaction might lead to better prediction ofrelapse as well as improved matching of patientsand treatments.

Chapter 4-Genetics 151

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Appendix A:The Drug Evaluation

Committee of theCollege on Problemsof Drug Dependence

The Comprehensive Drug Abuse Prevention andControl Act (PL 91-513) and the Psychotropic Sub-stances Act of 1978 (PL 95-633) gives exclusiveauthority to the Secretary of the Department of Healthand Human Services to determine the abuse liability ofsubstances and to make recommendations concerningtheir regulation and other drug policy decisions.Although the Secretary receives advice from the DrugEnforcement Agency (DEA), the Food and DrugAdministration (FDA), and various other regulatoryagencies, these laws explicitly state that the NationalInstitute on Drug Abuse (MDA) must provide to thesecretary information relevant to the abuse potential ofsuspected drugs of abuse and all information relevantto an assessment of their abuse potential. On the basisof this information from NIDA, and information fromFDA and DEA, the secretary makes a judgment as tothe dependence potential of new drugs.

NIDA’s role in providing information relevant tothe dependence liability of potential substances ofabuse has placed enormous demands on the Institute.The agency supports a variety of activities in commer-cial and private laboratories around the country toprovide this information. One of its principal sourcesof information comes from the College on Problems ofDrug Dependence (CPDD) and, specifically, its DrugEvaluation Committee (DEC). The relationship be-tween NIDA and CPDD is both formal and informal:NIDA provides over 98 percent of the funds requiredto assess the dependence liability of compounds inCPDD-sponsored testing facilities, NiDA is an officialliaison member of CPDD, and CPDD provides direct

input as requested in all NIDA decisions regarding thedependence potential of drugs.

Established in 1929, CPDD is the longest standinggroup in the country concerned with drug dependenceand abuse. It is an independent body, affiliated withmost scientific societies concerned with the depend-ence potential of abused substances and with regula-tory and governmental agencies such as the WorldHealth Organization (WHO), MDA, the NationalInstitute on Alcoholism and Alcohol Abuse, DEA, andFDA. Each of these agencies has formal ties withCPDD via liaison membership. In turn, CPDD pro-vides liaison representation to FDA and all otheragencies on request.

CPDD has three major functions: to assess the abuseliability of psychoactive drugs; to hold an annualscientific meeting to review the status of the depend-ence liability of drugs; and, to seine as a consultant tothe private sector and various governmental agencieson all drug-related matters and policies.

DEC oversees all aspects of CPDD’S dependenceliability testing program. DEC is devoted to researchon drugs of abuse and the determination of thedependence potential and abuse liability of specificclasses of drugs: analgesics, stimulants, and depres-sants. Governmental and regulatory agencies, such asNIDA, DEA, and FDA have relied on DEC forinformation on the abuse liability of opiate-likecompounds and stimulant and depressant drugs, Inaddition, CPDD is a collaborating center to WHO andprovides information about the abuse potential ofpharmaceuticals and scheduling worldwide. Produc-ing this information is generally beyond the capabili-

59


ties of third world countries. Finally, CPDD providesthe pharmaceutical industry and academic investiga-tors information on new and novel compounds in thedesign and development phase. Thus, the informationprovided plays an important role in scheduling drugs,drug policy making decisions, and the facilitation ofnew drug development.

Approximately 50 to 60 drugs per year are submit-ted by industry, academic institutions, National Insti-tutes of Health (NIH) laboratories, NIDA, WHO, andDEA (generally as a result of confiscation). A compu-terized list of submitted compounds is maintained atNIH; the code is broken only when testing is completetesting.

Appropriate quantities of the compounds aredistributed for testing to the various laboratories thatwork under the auspices of CPDD. The test results arereleased as soon as practical, but at most within 3 yearsof receipt of the compound. Information about thedrugs is confidential until one of three conditions issatisfied: the submittee grants explicit permission torelease the data; 3 years have elapsed or, Federaland/or regulatory organizations request CPDD toprovide information concerning the compound for thepublic welfare (e.g., a determination of whether thecompound should be scheduled under the ControlledSubstances Act prior to its marketing and distributionto humans).

Two university-based groups are involved withDEC’S evaluation of the analgesic types of drugs, andthree with evaluation of the stimulants and depres-sants. The Medical College of Virginia, VirginiaCommonwealth University, and the University ofMichigan Medical School examine analgesics, usingdifferent methods to discern the physical dependencepotential and abuse liability of presumed analgesics.Those two academic centers, along with the Missis-sippi Medical Center test stimulants and depressants.

‘The programs’ testing determines dependence lia-bility of drugs and, on request, carries out moredetailed studies to examine specific aspects of depend-ence liability, such as tolerance. For the last 30 years,this program has been largely responsible for obtainingbasic scientific information on specific classes ofcompounds and the mechanisms involved in theiracute and chronic pharmacological effects. DECreceives new compounds that are generally unavaila-ble to other testing groups and provides scientific dataon the pharmacology and abuse potential of newcompounds. Thus the program contributes to thedevelopment of new drugs and the understanding ofthe mechanismsdrugs.

underlying the abuse liability of

Appendix BAcknowledgments

OTA thanks the members of the advisory panel, contractors, and the many individuals and organizations thatsupplied information for this report, In addition, OTA acknowledges the following individuals for their commentson drafts of this report:

Mary AboodVirginia Commonwealth UniversityRichmond, VA

Martin AdlerTemple University School of MedicinePhiladelphia, PA

Robert BalsterVirginia Commonwealth UniversityRichmond, VA

Henry BegleiterState University of New YorkBrooklyn, NY

John CrabbeDepartment of Veterans Affairs Medical CenterPortland, OR

Stephen DinwiddieJewish Hospital of St. LouisSt. Louis, MO

Stephen DworkinWake Forest UniversityWinston-Salem, NC

Linda DykstraUniversity of North CarolinaChapel Hill, NC

R. Adron HarrisUniversity of Colorado Health Sciences CenterDenver, CO

Kenneth M. JohnsonUniversity of Texas Medical BranchGalveston, TX

William McBrideInstitute of Psychiatric ResearchIndianapolis, IN

Herman H. SamsonWake Forest UniversityWinston-Salem, NC

William WoolvertonUniversity of Mississippi Medical CenterJackson, MS

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