Physiology of Behavior 10e Ch04[1]

Psychopharmacology

■ Principles ofPsychopharmacologyPharmacokineticsDrug EffectivenessEffects of Repeated AdministrationPlacebo EffectsInterim Summary

■ Sites of Drug ActionEffects on Production of

NeurotransmittersEffects on Storage and Release

of NeurotransmittersEffects on ReceptorsEffects on Reuptake or Destruction

of NeurotransmittersInterim Summary

■ Neurotransmitters andNeuromodulatorsAcetylcholineThe MonoaminesAmino AcidsPeptidesLipidsNucleosidesSoluble GasesInterim Summary

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Physiology of Behavior, Tenth Edition, by Neil R. Carlson. Published by Allyn & Bacon. Copyright © 2010 by Pearson Education, Inc.

Psychopharmacology 103

Several years ago I spent the academic yearin a neurological research center affiliated with theteaching hospital at a medical center. One morning as I washaving breakfast, I read a brief item in the newspaper abouta man who had been hospitalized for botulism. Later thatmorning, I attended a weekly meeting during which the chiefof neurology discussed interesting cases presented by theneurological residents. I was surprised to see that we wouldvisit the man with botulism.

We entered the intensive care unit and saw that the manwas clearly on his way to recovery. His face was pale and hisvoice was weak, but he was no longer on a respirator. Therewasn’t much to see, so we went back to the lounge and dis-cussed his case.

Just before dinner a few days earlier, Mr. F. had openeda jar of asparagus that his family had canned. He noted rightaway that it smelled funny. Because his family had grown theasparagus in their own garden, he was reluctant to throw itaway. However, he decided that he wouldn’t take anychances. He dipped a spoon into the liquid in the jar andtouched it to his tongue. It didn’t taste right, so he didn’tswallow it. Instead, he stuck his tongue out and rinsed itunder a stream of water from the faucet at the kitchen sink.He dumped the asparagus into the garbage disposal.

About an hour later, as the family was finishing dinner,Mr. F. discovered that he was seeing double. Alarmed, he

asked his wife to drive him to the hospital. When he arrivedat the emergency room, he was seen by one of the neurolog-ical residents, who asked him, “Mr. F., you haven’t eatensome home-canned foods recently, have you?”

Learning that he had indeed let some liquid from a sus-pect jar of asparagus touch his tongue, the resident ordered avial of botulinum antitoxin from the pharmacy. Meanwhile, hetook a blood sample from Mr. F.’s vein and sent it to the lab forsome in vivo testing in mice. He then administered the anti-toxin, but already he could see that it was too late: Mr. F. wasshowing obvious signs of muscular weakness and was havingsome difficulty breathing. He was immediately sent to theintensive care unit, where he was put on a respirator. Althoughhe became completely paralyzed, the life support system didwhat its name indicates, and he regained control of his muscles.

What fascinated me the most was the in vivo testing pro-cedure for the presence of botulinum toxin in Mr. F.’s blood.Plasma extracted from the blood was injected into severalmice, half of which had been pretreated with botulinumantitoxin. The pretreated mice survived; the others all died.Just think: Mr. F. had touched only a few drops of the con-taminated liquid on his tongue and then rinsed it off imme-diately, but enough of the toxin entered his bloodstream thata small amount of his blood plasma could kill a mouse. Bythe way, we will examine the pharmacological effect of bot-ulinum toxin later in this chapter.

Chapter 2 introduced you to the cells of thenervous system, and Chapter 3 described itsbasic structure. Now it is time to build on thisinformation by introducing the field of psy-

chopharmacology. Psychopharmacology is the study ofthe effects of drugs on the nervous system and (ofcourse) on behavior. (Pharmakon is the Greek word for“drug.”)

But what is a drug? Like many words, this one hasseveral different meanings. In one context it refers to amedication that we would obtain from a pharmacist—a chemical that has a therapeutic effect on a disease orits symptoms. In another context the word refers to achemical that people are likely to abuse, such as heroinor cocaine. The meaning that will be used in this book(and the one generally accepted by pharmacologists)is “an exogenous chemical not necessary for normalcellular functioning that significantly alters the func-tions of certain cells of the body when taken in rela-tively low doses.” Because the topic of this chapter ispsychopharmacology, we will concern ourselves here onlywith chemicals that alter the functions of cells within thenervous system. The word exogenous rules out chemical mes-sengers produced by the body, such as neurotransmitters,

neuromodulators, or hormones. (Exogenous means “pro-duced from without”—that is, from outside the body.)Chemical messengers produced by the body are notdrugs, although synthetic chemicals that mimic theireffects are classified as drugs. The definition of a drugalso rules out essential nutrients, such as proteins, fats,carbohydrates, minerals, and vitamins that are a neces-sary constituent of a healthy diet. Finally, it states thatdrugs are effective in low doses. This qualification isimportant, because large quantities of almost anysubstance—even common ones such as table salt—willalter the functions of cells.

As we will see in this chapter, drugs have effects andsites of action. Drug effects are the changes we canobserve in an animal’s physiological processes andbehavior. For example, the effects of morphine, heroin,and other opiates include decreased sensitivity to pain,slowing of the digestive system, sedation, muscular

psychopharmacology The study of the effects of drugs on thenervous system and on behavior.

drug effect The changes a drug produces in an animal’sphysiological processes and behavior.

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104 Chapter 4 Psychopharmacology

relaxation, constriction of the pupils, and euphoria.The sites of action of drugs are the points at which mol-ecules of drugs interact with molecules located on or incells of the body, thus affecting some biochemicalprocesses of these cells. For example, the sites of actionof the opiates are specialized receptors situated in themembrane of certain neurons. When molecules of opi-ates attach to and activate these receptors, the drugsalter the activity of these neurons and produce theireffects. This chapter considers both the effects of drugsand their sites of action.

Psychopharmacology is an important field of neuro-science. It has been responsible for the development ofpsychotherapeutic drugs, which are used to treat psy-chological and behavioral disorders. It has also providedtools that have enabled other investigators to study thefunctions of cells of the nervous system and the behav-iors controlled by particular neural circuits.

This chapter does not contain all this book has tosay about the subject of psychopharmacology.Throughout the book you will learn about the use ofdrugs to investigate the nature of neural circuitsinvolved in the control of perception, memory, andbehavior. In addition, Chapters 16 and 17 discuss theuse of drugs to study and treat mental disorders such asschizophrenia, depression, and the anxiety disorders,and Chapter 18 discusses the physiology of drug abuse.

PRINCIPLES OFPSYCHOPHARMACOLOGY

This chapter begins with a description of the basic prin-ciples of psychopharmacology: the routes of administra-tion of drugs and their fate in the body. The second sec-tion discusses the sites of drug actions. The final sectiondiscusses specific neurotransmitters and neuromodula-tors and the physiological and behavioral effects of spe-cific drugs that interact with them.

PharmacokineticsTo be effective, a drug must reach its sites of action. Todo so, molecules of the drug must enter the body andthen enter the bloodstream so that they can be carriedto the organ (or organs) on which they act. Once there,they must leave the bloodstream and come into contactwith the molecules with which they interact. For almostall of the drugs we are interested in, this means that themolecules of the drug must enter the central nervoussystem (CNS). Some behaviorally active drugs exerttheir effects on the peripheral nervous system, but thesedrugs are less important to us than the drugs that affectcells of the CNS.

Molecules of drugs must cross several barriers to enterthe body and find their way to their sites of action. Somemolecules pass through these barriers easily and quickly;others do so very slowly. And once molecules of drugsenter the body, they begin to be metabolized—brokendown by enzymes—or excreted in the urine (or both). Intime, the molecules either disappear or are transformedinto inactive fragments. The process by which drugs areabsorbed, distributed within the body, metabolized, andexcreted is referred to as pharmacokinetics (“movementsof drugs”).

Routes of AdministrationFirst, let’s consider the routes by which drugs can beadministered. For laboratory animals the most commonroute is injection. The drug is dissolved in a liquid (or,in some cases, suspended in a liquid in the form of fineparticles) and injected through a hypodermic needle.The fastest route is intravenous (IV) injection—injectioninto a vein. The drug enters the bloodstream immedi-ately and reaches the brain within a few seconds. Thedisadvantages of IV injections are the increased careand skill they require in comparison to most otherforms of injection and the fact that the entire dosereaches the bloodstream at once. If an animal is espe-cially sensitive to the drug, there may be little time toadminister another drug to counteract its effects.

An intraperitoneal (IP) injection is rapid but not asrapid as an IV injection. The drug is injected throughthe abdominal wall into the peritoneal cavity—the spacethat surrounds the stomach, intestines, liver, and otherabdominal organs. IP injections are the most commonroute for administering drugs to small laboratory ani-mals. An intramuscular (IM) injection is made directlyinto a large muscle, such as those found in the upperarm, thigh, or buttocks. The drug is absorbed into thebloodstream through the capillaries that supply themuscle. If very slow absorption is desirable, the drug canbe mixed with another drug (such as ephedrine) thatconstricts blood vessels and retards the flow of blood

sites of action The locations at which molecules of drugs interactwith molecules located on or in cells of the body, thus affectingsome biochemical processes of these cells.

pharmacokinetics The process by which drugs are absorbed,distributed within the body, metabolized, and excreted.

intravenous (IV) injection Injection of a substance directly into a vein.

intraperitoneal (IP) injection (in tra pair i toe nee ul ) Injectionof a substance into the peritoneal cavity—the space that surroundsthe stomach, intestines, liver, and other abdominal organs.

intramuscular (IM) injection Injection of a substance into amuscle.

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Principles of Psychopharmacology 105

through the muscle. A drug can also be injected into thespace beneath the skin by means of a subcutaneous (SC)injection. A subcutaneous injection is useful only if smallamounts of drug need to be administered, because inject-ing large amounts would be painful. Some fat-solubledrugs can be dissolved in vegetable oil and administeredsubcutaneously. In this case, molecules of the drug willslowly leave the deposit of oil over a period of severaldays. If very slow and prolonged absorption of a drug isdesirable, the drug can be formed into a dry pellet orplaced in a sealed silicone rubber capsule and implant-ed beneath the skin.

Oral administration is the most common form ofadministering medicinal drugs to humans. Because ofthe difficulty of getting laboratory animals to eat some-thing that does not taste good to them, researchers sel-dom use this route. Some chemicals cannot be adminis-tered orally because they will be destroyed by stomachacid or digestive enzymes or because they are notabsorbed from the digestive system into the blood-stream. For example, insulin, a peptide hormone, mustbe injected. Sublingual administration of certain drugscan be accomplished by placing them beneath thetongue. The drug is absorbed into the bloodstream bythe capillaries that supply the mucous membrane thatlines the mouth. (Obviously, this method works onlywith humans, who will cooperate and leave the capsulebeneath their tongue.) Nitroglycerine, a drug that causesblood vessels to dilate, is taken sublingually by peoplewho suffer the pains of angina pectoris, caused byobstructions in the coronary arteries.

Drugs can also be administered at the opposite endof the digestive tract, in the form of suppositories.Intrarectal administration is rarely used to give drugs toexperimental animals. For obvious reasons this processwould be difficult with a small animal. In addition, whenagitated, small animals such as rats tend to defecate,which would mean that the drug would not remain inplace long enough to be absorbed. And I’m not sure Iwould want to try to administer a rectal suppository to alarge animal. Rectal suppositories are most commonlyused to administer drugs that might upset a person’sstomach.

The lungs provide another route for drug adminis-tration: inhalation. Nicotine, freebase cocaine, and mar-ijuana are usually smoked. In addition, drugs used totreat lung disorders are often inhaled in the form of avapor or fine mist, and many general anesthetics aregasses that are administered through inhalation. Theroute from the lungs to the brain is very short, anddrugs administered this way have very rapid effects.

Some drugs can be absorbed directly through theskin, so they can be given by means of topical administra-tion. Natural or artificial steroid hormones can be admin-istered in this way, as can nicotine (as a treatment to make

it easier for a person to stop smoking). The mucous mem-brane lining the nasal passages also provides a route fortopical administration. Commonly abused drugs such ascocaine hydrochloride are often sniffed so that they comeinto contact with the nasal mucosa. This route deliversthe drug to the brain very rapidly. (The technical, rarelyused name for this route is insufflation. And note thatsniffing is not the same as inhalation; when powderedcocaine is sniffed, it ends up in the mucous membrane ofthe nasal passages, not in the lungs.)

Finally, drugs can be administered directly into thebrain. As we saw in Chapter 2, the blood–brain barrierprevents certain chemicals from leaving capillaries andentering the brain. Some drugs cannot cross theblood–brain barrier. If these drugs are to reach thebrain, they must be injected directly into the brain orinto the cerebrospinal fluid in the brain’s ventricular sys-tem. To study the effects of a drug in a specific region ofthe brain (for example, in a particular nucleus of thehypothalamus), a researcher will inject a very smallamount of the drug directly into the brain. This proce-dure, known as intracerebral administration, isdescribed in more detail in Chapter 5. To achieve awidespread distribution of a drug in the brain, aresearcher will get past the blood–brain barrier byinjecting the drug into a cerebral ventricle. The drug isthen absorbed into the brain tissue, where it can exertits effects. This route, intracerebroventricular (ICV)administration, is used very rarely in humans—primarilyto deliver antibiotics directly to the brain to treat certaintypes of infections.

Figure 4.1 shows the time course of blood levels of acommonly abused drug, cocaine, after intravenousinjection, inhalation, oral administration, and sniffing.The amounts received were not identical, but the graphillustrates the relative rapidity with which the drugreaches the blood. (See Figure 4.1.)

subcutaneous (SC) injection Injection of a substance into thespace beneath the skin.

oral administration Administration of a substance into the mouthso that it is swallowed.

sublingual administration (sub ling wul ) Administration of asubstance by placing it beneath the tongue.

intrarectal administration Administration of a substance into therectum.

inhalation Administration of a vaporous substance into the lungs.

topical administration Administration of a substance directlyonto the skin or mucous membrane.

intracerebral administration Administration of a substancedirectly into the brain.

intracerebroventricular (ICV) administration Administration ofa substance into one of the cerebral ventricles.

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Distribution of Drugs Within the BodyAs we saw, drugs exert their effects only when they reachtheir sites of action. In the case of drugs that affectbehavior, most of these sites are located on or in partic-ular cells in the central nervous system. The previoussection described the routes by which drugs can beintroduced into the body. With the exception of intra-cerebral or intracerebroventricular administration theroutes of drug administration vary only in the rate atwhich a drug reaches the blood plasma (that is, the liq-uid part of the blood). But what happens next? All thesites of action of drugs of interest to psychopharmacolo-gists lie outside the blood vessels.

Several factors determine the rate at which a drugin the bloodstream reaches sites of action within thebrain. The first is lipid solubility. The blood–brain barrieris a barrier only for water-soluble molecules. Moleculesthat are soluble in lipids pass through the cells that linethe capillaries in the central nervous system, and theyrapidly distribute themselves throughout the brain. Forexample, diacetylmorphine (more commonly known asheroin) is more lipid soluble than morphine is. Thus, anintravenous injection of heroin produces more rapideffects than does one of morphine. Even though themolecules of the two drugs are equally effective whenthey reach their sites of action in the brain, the fact thatheroin molecules get there faster means that they pro-duce a more intense “rush,” and this explains why drugaddicts prefer heroin to morphine.

Many drugs bind with various tissues of the body orwith proteins in the blood—a phenomenon known asdepot binding. As long as the molecules of the drug arebound to a depot, they cannot reach their sites of actionand cannot exert their effects. One source of such bind-ing is albumin, a protein found in the blood. Albuminserves to transport free fatty acids, a source of nutrientsfor most cells of the body, but this protein can also bindwith some lipid-soluble drugs. Depot binding can bothdelay and prolong the effects of a drug. Consider a lipid-soluble drug taken orally. As molecules of the drug areabsorbed from the stomach, they begin to bind withalbumin in the blood. For a while, very little of the drugreaches the brain. Finally, the albumin molecules canhold no more of the drug, so it begins to enter thebrain. Eventually, all the drug is absorbed from thestomach. Then, perhaps over a period of several hours,the albumin molecules gradually release the moleculesof the drug as the plasma concentration of the drugfalls. (See Figure 4.2.)

Other sources of depot binding include fat tissue,bones, muscles, and the liver. Of course, drugs bind withthese depots more slowly than they do with albumin,because they must leave the blood vessels to do so. Thus,these sources of binding are less likely to interfere withthe initial effects of a drug. For example, thiopental, abarbiturate that is sometimes used to anesthetize thebrain, has high lipid solubility. An intravenous injectionof this drug reaches the brain within a few seconds afterbeing injected intravenously. The drug also binds verywell with muscles and fat tissue, so it soon is taken out ofcirculation, and the levels of the drug in the brain fallrapidly. Within 30 minutes or so, the drug’s anestheticeffect is gone. Eventually, the drug is destroyed byenzymes and excreted by the kidneys.

Inactivation and ExcretionDrugs do not remain in the body indefinitely. Many aredeactivated by enzymes, and all are eventually excreted,primarily by the kidneys. The liver plays an especiallyactive role in enzymatic deactivation of drugs, but somedeactivating enzymes are also found in the blood. Thebrain also contains enzymes that destroy some drugs. Insome cases, enzymes transform molecules of a drug intoother forms that themselves are biologically active.Occasionally, the transformed molecule is even moreactive than the one that is administered. In such casesthe effects of a drug can have a very long duration.

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FIGURE 4.1 ■ Cocaine in Blood Plasma .

The graph shows the concentration of cocaine in bloodplasma after intravenous injection, inhalation, oraladministration, and sniffing.

(Adapted from Feldman, R. S., Meyer, J. S., and Quenzer, L. F. Principles ofNeuropsychopharmacology. Sunderland, MA: Sinauer Associates,1997; afterJones, R. T. NIDA Research Monographs, 1990, 99, 30–41.)

depot binding Binding of a drug with various tissues of the bodyor with proteins in the blood.

albumin (al bew min) A protein found in the blood; serves totransport free fatty acids and can bind with some lipid-solubledrugs.

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Stomach

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Bloodstream

BrainAlbumin Drug bound

with albumin

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(b)

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FIGURE 4.2 ■ Depot Binding with Blood .Albumin Protein .

(a) The drug begins to be absorbed from the stomach intothe bloodstream, where it binds with albumin. (b) Thealbumin molecules are saturated with the drug and canhold no more. (c) Unbound molecules of the drug begin toenter the brain. Eventually, molecules of the drug will breakaway from the molecules of albumin and enter the brain.

ineffective drug. The best way to measure the effective-ness of a drug is to plot a dose-response curve. To dothis, subjects are given various doses of a drug, usuallydefined as milligrams of drug per kilogram of a subject’sbody weight, and the effects of the drug are plotted.Because the molecules of most drugs distribute them-selves throughout the blood and then throughout therest of the body, a heavier subject (human or laboratoryanimal) will require a larger quantity of a drug toachieve the same concentration as a smaller quantitywill produce in a smaller subject. As Figure 4.3 shows,increasingly stronger doses of a drug cause increasinglylarger effects until the point of maximum effect isreached. At this point, increasing the dose of the drugdoes not produce any more effect. (See Figure 4.3.)

Most drugs have more than one effect. Opiates suchas morphine and codeine produce analgesia (reducedsensitivity to pain), but they also depress the activity ofneurons in the medulla that control heart rate and res-piration. A physician who prescribes an opiate to relievea patient’s pain wants to administer a dose that is largeenough to produce analgesia but not large enough todepress heart rate and respiration—effects that could befatal. Figure 4.4 shows two dose-response curves, one forthe analgesic effects of a painkiller and one for thedrug’s depressant effects on respiration. The differencebetween these curves indicates the drug’s margin of

FIGURE 4.3 ■ A Dose-Response Curve .

Increasingly stronger doses of the drug produce increasinglylarger effects until the maximum effect is reached. After that point, increments in the dose do not produce anyincrements in the drug’s effect. However, the risk of adverseside effects increases.

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After this point,increasing the dosedoes not producea stronger effect

Drug EffectivenessDrugs vary widely in their effectiveness. The effects of asmall dose of a relatively effective drug can equal orexceed the effects of larger amounts of a relatively

dose-response curve A graph of the magnitude of an effect of adrug as a function of the amount of drug administered.

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safety. Obviously, the most desirable drugs have a largemargin of safety. (See Figure 4.4.)

One measure of a drug’s margin of safety is itstherapeutic index. This measure is obtained by adminis-tering varying doses of the drug to a group of laboratoryanimals such as mice. Two numbers are obtained: thedose that produces the desired effects in 50 percent ofthe animals and the dose that produces toxic effects in50 percent of the animals. The therapeutic index is theratio of these two numbers. For example, if the toxicdose is five times higher than the effective dose, thenthe therapeutic index is 5.0. The lower the therapeuticindex, the more care must be taken in prescribing thedrug. For example, barbiturates have relatively low ther-apeutic indexes—as low as 2 or 3. In contrast, tranquil-izers such as Valium have therapeutic indexes of wellover 100. As a consequence, an accidental overdose of abarbiturate is much more likely to have tragic effectsthan a similar overdose of or Valium.

Why do drugs vary in their effectiveness? There aretwo reasons. First, different drugs—even those with thesame behavioral effects—may have different sites ofaction. For example, both morphine and aspirin haveanalgesic effects, but morphine suppresses the activity ofneurons in the spinal cord and brain that are involved

in pain perception, whereas aspirin reduces the produc-tion of a chemical involved in transmitting informationfrom damaged tissue to pain-sensitive neurons. Becausethe drugs act very differently, a given dose of morphine(expressed in terms of milligrams of drug per kilogramof body weight) produces much more pain reductionthan the same dose of aspirin does.

The second reason that drugs vary in their effec-tiveness has to do with the affinity of the drug with itssite of action. As we will see in the next major sectionof this chapter, most drugs of interest to psychophar-macologists exert their effects by binding with othermolecules located in the central nervous system—withpresynaptic or postsynaptic receptors, with transportermolecules, or with enzymes involved in the productionor deactivation of neurotransmitters. Drugs vary widelyin their affinity for the molecules to which theyattach—the readiness with which the two moleculesjoin together. A drug with a high affinity will produceeffects at a relatively low concentration, whereas a drugwith a low affinity must be administered in relativelyhigh doses. Thus, even two drugs with identical sites ofaction can vary widely in their effectiveness if they havedifferent affinities for their binding sites. In addition,because most drugs have multiple effects, a drug canhave high affinities for some of its sites of action andlow affinities for others. The most desirable drug has ahigh affinity for sites of action that produce therapeu-tic effects and a low affinity for sites of action that pro-duce toxic side effects. One of the goals of research bydrug companies is to find chemicals with just this pat-tern of effects.

Effects of Repeated AdministrationOften, when a drug is administered repeatedly, itseffects will not remain constant. In most cases its effectswill diminish—a phenomenon known as tolerance. Inother cases a drug becomes more and more effective—a phenomenon known as sensitization.

Let’s consider tolerance first. Tolerance is seen inmany drugs that are commonly abused. For example, aregular user of heroin must take larger and largeramounts of the drug for it to be effective. And once aperson has taken an opiate regularly enough to develop

FIGURE 4.4 ■ Dose Response Curves .for Morphine .

The dose-response curve on the left shows the analgesiceffect of morphine, and the curve on the right shows one ofthe drug’s adverse side effects: its depressant effect onrespiration. A drug’s margin of safety is reflected by thedifference between the dose-response curve for itstherapeutic effects and that for its adverse side effects.

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Dose-responsecurve for theanalgesic effectof morphine

Dose-responsecurve for thedepressive effectof morphine onrespiration

therapeutic index The ratio between the dose that produces thedesired effect in 50 percent of the animals and the dose thatproduces toxic effects in 50 percent of the animals.

affinity The readiness with which two molecules join together.

tolerance A decrease in the effectiveness of a drug that isadministered repeatedly.

sensitization An increase in the effectiveness of a drug that isadministered repeatedly.

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tolerance, that individual will suffer withdrawal symp-toms if he or she suddenly stops taking the drug.Withdrawal symptoms are primarily the opposite of theeffects of the drug itself. For example, heroin produceseuphoria; withdrawal from it produces dysphoria—a feel-ing of anxious misery. (Euphoria and dysphoria mean“easy to bear” and “hard to bear,” respectively.) Heroinproduces constipation; withdrawal from it producesnausea and cramping. Heroin produces relaxation;withdrawal from it produces agitation.

Withdrawal symptoms are caused by the same mech-anisms that are responsible for tolerance. Tolerance is theresult of the body’s attempt to compensate for the effectsof the drug. That is, most systems of the body, includingthose controlled by the brain, are regulated so that theystay at an optimal value. When the effects of a drug alterthese systems for a prolonged time, compensatory mech-anisms begin to produce the opposite reaction, at leastpartially compensating for the disturbance from the opti-mal value. These mechanisms account for the fact thatmore and more of the drug must be taken to achieve agiven level of effects. Then, when the person stops takingthe drug, the compensatory mechanisms make them-selves felt, unopposed by the action of the drug.

Research suggests that there are several types ofcompensatory mechanisms. As we will see, many drugsthat affect the brain do so by binding with receptors andactivating them. The first compensatory mechanisminvolves a decrease in the effectiveness of such binding.Either the receptors become less sensitive to the drug(that is, their affinity for the drug decreases) or thereceptors decrease in number. The second compensa-tory mechanism involves the process that couples thereceptors to ion channels in the membrane or to theproduction of second messengers. After prolonged stim-ulation of the receptors, one or more steps in the cou-pling process become less effective. (Of course, botheffects can occur.) The details of these compensatorymechanisms are described in Chapter 18, which dis-cusses the causes and effects of drug abuse.

As we saw, many drugs have several different sitesof action and thus produce several different effects.This means that some of the effects of a drug may showtolerance but others may not. For example, barbitu-rates cause sedation and also depress neurons that con-trol respiration. The sedative effects show tolerance,but the respiratory depression does not. This meansthat if larger and larger doses of a barbiturate are takento achieve the same level of sedation, the person beginsto run the risk of taking a dangerously large dose of thedrug.

Sensitization is, of course, the exact opposite of tol-erance: Repeated doses of a drug produce larger andlarger effects. Because compensatory mechanisms tendto correct for deviations away from the optimal values of

physiological processes, sensitization is less commonthan tolerance. And some of the effects of a drug mayshow sensitization while others show tolerance. Forexample, repeated injections of cocaine become moreand more likely to produce movement disorders andconvulsions, whereas the euphoric effects of the drug donot show sensitization—and may even show tolerance.

Placebo EffectsA placebo is an innocuous substance that has no specif-ic physiological effect. The word comes from the Latinplacere, “to please.” A physician may sometimes give aplacebo to anxious patients to placate them. (You cansee that the word placate also has the same root.) Butalthough placebos have no specific physiological effect,it is incorrect to say that they have no effect. If a personthinks that a placebo has a physiological effect, thenadministration of the placebo may actually producethat effect.

When experimenters want to investigate the behav-ioral effects of drugs in humans, they must use controlgroups whose members receive placebos, or they cannotbe sure that the behavioral effects they observe werecaused by specific effects of the drug. Studies with labo-ratory animals must also use placebos, even though weneed not worry about the animals’ “beliefs” about theeffects of the drugs we give them. Consider what youmust do to give a rat an intraperitoneal injection of adrug. You reach into the animal’s cage, pick the animalup, hold it in such a way that its abdomen is exposedand its head is positioned to prevent it from biting you,insert a hypodermic needle through its abdominal wall,press the plunger of the syringe, and replace the animalin its cage, being sure to let go of it quickly so that it can-not turn and bite you. Even if the substance you inject isinnocuous, the experience of receiving the injectionwould activate the animal’s autonomic nervous system,cause the secretion of stress hormones, and have otherphysiological effects. If we want to know what the behav-ioral effects of a drug are, we must compare the drug-treated animals with other animals who receive a placebo,administered in exactly the same way as the drug. (Bythe way, a skilled and experienced researcher can han-dle a rat so gently that it shows very little reaction to ahypodermic injection.)

withdrawal symptom The appearance of symptoms opposite tothose produced by a drug when the drug is administered repeatedlyand then suddenly no longer taken.

placebo (pla see boh) An inert substance that is given to anorganism in lieu of a physiologically active drug; used experimentallyto control for the effects of mere administration of a drug.

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SITES OF DRUG ACTIONThroughout the history of our species, people have dis-covered that plants—and a few animals—producechemicals that act on synapses. (Of course, the peoplewho discovered these chemicals knew nothing aboutneurons and synapses.) Some of these chemicals havebeen used for their pleasurable effects; others have beenused to treat illness, reduce pain, or poison other ani-mals (or enemies). More recently, scientists havelearned to produce completely artificial drugs, somewith potencies far greater than those of the naturallyoccurring drugs. The traditional uses of drugs remain,but in addition, they can be used in research laborato-ries to investigate the operations of the nervous system.Most drugs that affect behavior do so by affecting synap-tic transmission. Drugs that affect synaptic transmissionare classified into two general categories. Those thatblock or inhibit the postsynaptic effects are calledantagonists. Those that facilitate them are calledagonists. (The Greek word agon means “contest.” Thus,an agonist is one who takes part in the contest.)

This section will describe the basic effects ofdrugs on synaptic activity. Recall from Chapter 2 that

the sequence of synaptic activity goes like this:Neurotransmitters are synthesized and stored in synap-tic vesicles. The synaptic vesicles travel to the presynap-tic membrane, where they become docked. When anaxon fires, voltage-dependent calcium channels in thepresynaptic membrane open, permitting the entry ofcalcium ions. The calcium ions interact with the dock-ing proteins and initiate the release of the neurotrans-mitters into the synaptic cleft. Molecules of the neuro-transmitter bind with postsynaptic receptors, causingparticular ion channels to open, which produces excita-tory or inhibitory postsynaptic potentials. The effects ofthe neurotransmitter are kept relatively brief by theirreuptake by transporter molecules in the presynapticmembrane or by their destruction by enzymes. In addi-tion, the stimulation of presynaptic autoreceptors regu-lates the synthesis and release of the neurotransmitter.The discussion of the effects of drugs in this section

InterimSummaryPrinciples of PsychopharmacologyPsychopharmacology is the study of the effects of drugs onthe nervous system and behavior. Drugs are exogenous chem-icals that are not necessary for normal cellular functioningthat significantly alter the functions of certain cells of thebody when taken in relatively low doses. Drugs have effects,physiological and behavioral, and they have sites of action—molecules with which they interact to produce these effects.

Pharmacokinetics is the fate of a drug as it is absorbedinto the body, circulates throughout the body, and reaches itssites of action. Drugs may be administered by intravenous,intraperitoneal, intramuscular, and subcutaneous injection;they may be administered orally, sublingually, intrarectally,by inhalation, and topically (on skin or mucous membrane);and they may be injected intracerebrally or intracerebroven-tricularly. Lipid-soluble drugs easily pass through theblood–brain barrier, whereas others pass this barrier slowlyor not at all.

The time courses of various routes of drug administra-tion are different. And once molecules of a drug reach the

antagonist A drug that opposes or inhibits the effects of aparticular neurotransmitter on the postsynaptic cell.

agonist A drug that facilitates the effects of a particularneurotransmitter on the postsynaptic cell.

blood, they may bind with albumin protein, and they maybind with storage depots in fat tissue, muscles, or bones.Eventually, drugs disappear from the body. Some are deacti-vated by enzymes, especially in the liver, and others are sim-ply excreted.

The dose-response curve represents a drug’s effective-ness; it relates the amount administered (usually in mil-ligrams per kilogram of the subject’s body weight) to theresulting effect. Most drugs have more than one site of actionand thus more than one effect. The safety of a drug is mea-sured by the difference between doses that produce desirableeffects and those that produce toxic side effects. Drugs varyin their effectiveness because of the nature of their sites ofactions and the affinity between molecules of the drug andthese sites of action.

Repeated administration of a drug can cause either tol-erance, often resulting in withdrawal symptoms, or sensitiza-tion. Tolerance can be caused by decreased affinity of a drugwith its receptors, by decreased numbers of receptors, or bydecreased coupling of receptors with the biochemical steps itcontrols. Some of the effects of a drug may show tolerance,while others may not—or may even show sensitization.

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Sites of Drug Action 111

follows the same basic sequence. All of the effects I willdescribe are summarized in Figure 4.5, with somedetails shown in additional figures. I should warn you

that some of the effects arecomplex, so the discussion thatfollows bears careful reading. Irecommend that you studyMyPsychKit 4.1, Actions of Drugs,which reviews this material.

Effects on Production ofNeurotransmittersThe first step is the synthesis of the neurotransmitterfrom its precursors. In some cases the rate of synthesisand release of a neurotransmitter is increased when aprecursor is administered; in these cases the precursoritself serves as an agonist. (See step 1 in Figure 4.5.)

The steps in the synthesis of neurotransmitters arecontrolled by enzymes. Therefore, if a drug inactivatesone of these enzymes, it will prevent the neurotransmit-ter from being produced. Such a drug serves as anantagonist. (See step 2 in Figure 4.5.)

Effects on Storage and Release of NeurotransmittersNeurotransmitters are stored in synaptic vesicles, whichare transported to the presynaptic membrane, where thechemicals are released. The storage of neurotransmittersin vesicles is accomplished by the same kind of trans-porter molecules that are responsible for reuptake of aneurotransmitter into a terminal button. The trans-porter molecules are located in the membrane of synap-tic vesicles, and their action is to pump molecules of theneurotransmitter across the membrane, filling the vesi-cles. Some of the transporter molecules that fill synapticvesicles are capable of being blocked by a drug.Molecules of the drug bind with a particular site on thetransporter and inactivate it. Because the synaptic vesiclesremain empty, nothing is released when the vesicles even-tually rupture against the presynaptic membrane. Thedrug serves as an antagonist. (See step 3 in Figure 4.5.)

Some drugs act as antagonists by preventing therelease of neurotransmitters from the terminal button.They do so by deactivating the proteins that causedocked synaptic vesicles to fuse with the presynaptic

3

1

4

5

6

7

2

11 Drug inactivates acetylcholinesterase

AGO(e.g., physostigmine—ACh)

10 Drug blocks reuptakeAGO

(e.g., cocaine—dopamine)

9 Drug blocks autoreceptors;increases synthesis/release of NT

AGO(e.g., idazoxan—norepinephrine)

8

Drug serves as precursorAGO

(e.g., L-DOPA–dopamine)

Drug prevents storage of NT in vesiclesANT

(e.g., reserpine–monoamines)

Drug stimulates release of NTAGO

(e.g., black widow spider venom–ACh)

Drug inhibits release of NTANT

(e.g., botulinum toxin–ACh)

Drug stimulatespostsynaptic receptors

AGO(e.g., nicotine, muscarine–ACh)

Drug blockspostsynaptic receptors

ANT(e.g., curare, atropine–ACh)

Molecules ofdrugs

Drug inactivates synthetic enzyme;inhibits synthesis of NT

ANT(e.g., PCPA–serotonin)

Drug stimulates autoreceptors;inhibits synthesis/release of NT

ANT(e.g., apomorphine—dopamine)

Precursor

Enzyme

Neurotransmitter

Inhibition

Choline+

acetate

AChAChE

FIGURE 4.5 ■ Drug Affects on Synaptic Transmission .

The figure summarizes the ways in which drugs can affect the synaptic transmission(AGO agonist; ANT antagonist; NT neurotransmitter). Drugs that act as agonists aremarked in blue; drugs that act as antagonists are marked in red.

===

Animation 4.1Actions of Drugs

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membrane and expel their contents into the synapticcleft. Other drugs have just the opposite effect: They actas agonists by binding with these proteins and directlytriggering release of the neurotransmitter. (See steps 4and 5 in Figure 4.5.)

Effects on ReceptorsThe most important—and most complex—site of actionof drugs in the nervous system is on receptors, bothpresynaptic and postsynaptic. Let’s consider postsynap-tic receptors first. (Here is where the careful readingshould begin.) Once a neurotransmitter is released, itmust stimulate the postsynaptic receptors. Some drugsbind with these receptors, just as the neurotransmitterdoes. Once a drug has bound with the receptor, it canserve as either an agonist or an antagonist.

A drug that mimics the effects of a neurotransmitteracts as a direct agonist. Molecules of the drug attach tothe binding site to which the neurotransmitter normallyattaches. This binding causes ion channels controlled bythe receptor to open, just as they do when the neuro-transmitter is present. Ions then pass through thesechannels and produce postsynaptic potentials. (See step6 in Figure 4.5.)

Drugs that bind with postsynaptic receptors can alsoserve as antagonists. Molecules of such drugs bind withthe receptors but do not open the ion channel. Becausethey occupy the receptor’s binding site, they prevent theneurotransmitter from opening the ion channel. Thesedrugs are called receptor blockers or direct antagonists.(See step 7 in Figure 4.5.)

Some receptors have multiple binding sites, to whichdifferent ligands can attach. Molecules of the neurotrans-mitter bind with one site, and other substances (such asneuromodulators and various drugs) bind with the others.

Binding of a molecule with one of these alternative sitesis referred to as noncompetitive binding, because themolecule does not compete with molecules of the neuro-transmitter for the same binding site. If a drug attachesto one of these alternative sites and prevents the ionchannel from opening, the drug is said to be an indirectantagonist. The ultimate effect of an indirect antagonist issimilar to that of a direct antagonist, but its site of actionis different. If a drug attaches to one of the alternativesites and facilitates the opening of the ion channel, it issaid to be an indirect agonist. (See Figure 4.6.)

As we saw in Chapter 2, the presynaptic membranesof some neurons contain autoreceptors that regulatethe amount of neurotransmitter that is released.Because stimulation of these receptors causes less neu-rotransmitter to be released, drugs that selectively acti-vate presynaptic receptors act as antagonists. Drugs thatblock presynaptic autoreceptors have the opposite effect:They increase the release of the neurotransmitter, actingas agonists. (Refer to steps 8 and 9 in Figure 4.5.)

We also saw in Chapter 2 that some terminal buttonsform axoaxonic synapses—synapses of one terminal

Neurotransmitterbinding site

Drug Drug Drug Drug

NoncompetitiveBinding

Neuromodulatorbinding site

Indirectantagonist

Indirectagonist

Directantagonist

Directagonist

(a) (b)

Neuro-transmitter

Neuro-transmitter

CompetitiveBinding

FIGURE 4.6 ■ Drug Actions at Binding Sites .

(a) Competitive binding: Direct agonists and antagonists act directly on theneurotransmitter binding site. (b) Noncompetitive binding: Indirect agonists andantagonists act on an alternative binding site and modify the effects of theneurotransmitter on opening of the ion channel.

direct agonist A drug that binds with and activates a receptor.

receptor blocker A drug that binds with a receptor but does notactivate it; prevents the natural ligand from binding with the receptor.

direct antagonist A synonym for receptor blocker.

noncompetitive binding Binding of a drug to a site on a receptor;does not interfere with the binding site for the principal ligand.

indirect antagonist A drug that attaches to a binding site on areceptor and interferes with the action of the receptor; does notinterfere with the binding site for the principal ligand.

indirect agonist A drug that attaches to a binding site on areceptor and facilitates the action of the receptor; does not interferewith the binding site for the principal ligand.

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Sites of Drug Action 113

FIGURE 4.8 ■ Dendritic Autoreceptors .

The dendrites of certain neurons release someneurotransmitter when the cell is active. Activation ofdendritic autoreceptors by the neurotransmitter (or by adrug that binds with these receptors) hyperpolarizes themembrane, reducing the neuron’s rate of firing. Blocking ofdendritic autoreceptors by a drug prevents this effect.

Molecule ofneurotransmitterreleased by dendritewhen neuronbecomes active

Cell body

Nucleus

Dendriticautoreceptor

Activation of dendriticautoreceptors producesa hyperpolarization

FIGURE 4.7 ■ Presynaptic Heteroreceptors .

Presynaptic facilitation is caused by activation of receptorsthat facilitate the opening of calcium channels near theactive zone of the postsynaptic terminal button, whichpromotes release of the neurotransmitter. Presynapticinhibition is caused by activation of receptors that inhibitthe opening of these calcium channels.

Molecule of drug thatactivates presynapticheteroreceptors

Presynapticheteroreceptor

Presynapticinhibition: Openingof calcium channelsis inhibited

Synapticvesicle

Presynapticterminal button

Postsynapticterminal button

Calcium channels mustopen to permit the releaseof the neurotransmitter

Postsynapticreceptor

Presynapticfacilitation: Openingof calcium channelsis facilitated

button with another. Activation of the first terminal but-ton causes presynaptic inhibition or facilitation of thesecond one. The second terminal button containspresynaptic heteroreceptors, which are sensitive to theneurotransmitter released by the first one. (Auto means“self”; hetero means “other.”) Presynaptic heteroreceptorsthat produce presynaptic inhibition do so by inhibitingthe release of the neurotransmitter. Conversely, presy-naptic heteroreceptors responsible for presynaptic facili-tation facilitate the release of the neurotransmitter. Sodrugs can block or facilitate presynaptic inhibition orfacilitation, depending on whether they block or activatepresynaptic heteroreceptors. (See Figure 4.7.)

Finally (yes, this is the last site of action I willdescribe in this subsection), you will recall from Chapter2 that autoreceptors are located in the membrane ofdendrites of some neurons. When these neuronsbecome active, their dendrites, as well as their terminal

buttons, release neurotransmitter. The neurotransmit-ter released by the dendrites stimulates autoreceptorslocated on these same dendrites, which decrease neuralfiring by producing hyperpolarizations. This mecha-nism has a regulatory effect, serving to prevent theseneurons from becoming too active. Thus, drugs thatbind with and activate dendritic autoreceptors will serveas antagonists. Those that bind with and block dendriticautoreceptors will serve as agonists, because they will pre-vent the inhibitory hyperpolarizations. (See Figure 4.8.)

As you will surely realize, the effects of a particulardrug that binds with a particular type of receptor can bevery complex. The effects depend on where the recep-tor is located, what its normal effects are, and whetherthe drug activates the receptor or blocks its actions.

Effects on Reuptake or Destruction of NeurotransmittersThe next step after stimulation of the postsynapticreceptor is termination of the postsynaptic potential.Two processes accomplish that task: Molecules of theneurotransmitter are taken back into the terminal

presynaptic heteroreceptor A receptor located in the membraneof a terminal button that receives input from another terminalbutton by means of an axoaxonic synapse; binds with theneurotransmitter released by the presynaptic terminal button.

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button through the process of reuptake, or they aredestroyed by an enzyme. Drugs can interfere with eitherof these processes. In the first case, molecules of thedrug attach to the transporter molecules responsible forreuptake and inactivate them, thus blocking reuptake.In the second case, molecules of the drug bind with theenzyme that normally destroys the neurotransmitter

and prevents the enzymes from working. The mostimportant example of such an enzyme is acetyl-cholinesterase, which destroys acetylcholine. Becauseboth types of drugs prolong the presence of the neuro-transmitter in the synaptic cleft (and hence in a locationwhere they can stimulate postsynaptic receptors), theyserve as agonists. (Refer to steps 10 and 11 in Figure 4.5.)

InterimSummarySites of Drug ActionThe process of synaptic transmission entails the synthesis ofthe neurotransmitter, its storage in synaptic vesicles, itsrelease into the synaptic cleft, its interaction with post-synaptic receptors, and the consequent opening of ionchannels in the postsynaptic membrane. The effects of theneurotransmitter are then terminated by reuptake into theterminal button or, in the case of acetylcholine, by enzy-matic deactivation.

Each of the steps necessary for synaptic transmission canbe interfered with by drugs that serve as antagonists, and afew can be stimulated by drugs that serve as agonists. Thus,

NEUROTRANSMITTERS ANDNEUROMODULATORS

Because neurotransmitters have two general effects onpostsynaptic membranes—depolarization (EPSP) orhyperpolarization (IPSP)—one might expect that therewould be two kinds of neurotransmitters, excitatoryand inhibitory. Instead, there are many differentkinds—several dozen at least. In the brain most synap-tic communication is accomplished by two neurotrans-mitters: one with excitatory effects (glutamate) and onewith inhibitory effects (GABA). (Another inhibitoryneurotransmitter, glycine, is found in the spinal cordand lower brain stem.) Most of the activity of local cir-cuits of neurons involves balances between the excitato-ry and inhibitory effects of these chemicals, which areresponsible for most of the information transmittedfrom place to place within the brain. In fact, there areprobably no neurons in the brain that do not receiveexcitatory input from glutamate-secreting terminal but-tons and inhibitory input from neurons that secreteeither GABA or glycine. And with the exception ofneurons that detect painful stimuli, all sensory organstransmit information to the brain through axons whoseterminals release glutamate. (Pain-detecting neuronssecrete a peptide.)

What do all the other neurotransmitters do? In gen-eral, they have modulating effects rather than informa-tion-transmitting effects. That is, the release of neuro-transmitters other than glutamate and GABA tends toactivate or inhibit entire circuits of neurons that areinvolved in particular brain functions. For example,secretion of acetylcholine activates the cerebral cortexand facilitates learning, but the information that islearned and remembered is transmitted by neurons thatsecrete glutamate and GABA. Secretion of norepineph-rine increases vigilance and enhances readiness to actwhen a signal is detected. Secretion of serotonin sup-presses certain categories of species-typical behaviorsand reduces the likelihood that the animal acts impul-sively. Secretion of dopamine in some regions of thebrain generally activates voluntary movements but doesnot specify which movements will occur. In otherregions, secretion of dopamine reinforces ongoingbehaviors and makes them more likely to occur at a latertime. Because particular drugs can selectively affect neu-rons that secrete particular neurotransmitters, they canhave specific effects on behavior.

This section introduces the most important neuro-transmitters, discusses some of their behavioral func-tions, and describes the drugs that interact with them.As we saw in the previous section of this chapter, drugshave many different sites of action. Fortunately for your

drugs can increase the pool of available precursor, block abiosynthetic enzyme, prevent the storage of neurotransmit-ter in synaptic vesicles, stimulate or block the release of theneurotransmitter, stimulate or block presynaptic or post-synaptic receptors, retard reuptake, or deactivate enzymesthat destroy the neurotransmitter. A drug that activates post-synaptic receptors serves as an agonist, whereas one thatactivates presynaptic or dendritic autoreceptors or serves asan antagonist. A drug that blocks postsynaptic receptorsserves as an antagonist, whereas one that blocks autorecep-tors serves as an agonist. A drug that activates or blockspresynaptic heteroreceptors serves as an agonist or antago-nist, depending on whether the heteroreceptors are respon-sible for presynaptic facilitation or inhibition.

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Neurotransmitters and Neuromodulators 115

information-processing capacity (and perhaps your san-ity), not all types of neurons are affected by all types ofdrugs. As you will see, that still leaves a good number ofdrugs to be mentioned by name. Obviously, some aremore important than others. Those whose effects Idescribe in some detail are more important than those Imention in passing. If you want to learn more detailsabout these drugs (and many others), you should con-sult one of the psychopharmacology texts listed in thesuggested readings at the end of this chapter.

AcetylcholineAcetylcholine is the primary neurotransmitter secretedby efferent axons of the peripheral nervous system. Allmuscular movement is accomplished by the release ofacetylcholine, and ACh is also found in the ganglia ofthe autonomic nervous system and at the target organsof the parasympathetic branch of the ANS. Because AChis found outside the central nervous system in locationsthat are easy to study, this neurotransmitter was thefirst to be discovered, and it has received much atten-tion from neuroscientists. Some terminology: Thesesynapses are said to be acetylcholinergic. Ergon is the Greekword for “work.” Thus, dopaminergic synapses releasedopamine, serotonergic synapses release serotonin, and soon. (The suffix -ergic is pronounced “ur jik”.)

The axons and terminal buttons of acetylcholiner-gic neurons are distributed widely throughout thebrain. Three systems have received the most attentionfrom neuroscientists: those originating in the dorsolat-eral pons, the basal forebrain, and the medial septum.The effects of ACh release in the brain are generallyfacilitatory. The acetylcholinergic neurons located inthe dorsolateral pons play a role in REM sleep (thephase of sleep during which dreaming occurs). Thoselocated in the basal forebrain are involved in activatingthe cerebral cortex and facilitating learning, especiallyperceptual learning. Those located in the medial sep-tum control the electrical rhythms of the hippocampusand modulate its functions, which include the forma-tion of particular kinds of memories.

Figure 4.9 shows a schematic midsagittal view of arat brain. On it are indicated the most important sites ofacetylcholinergic cell bodies and the regions served bythe branches of their axons. The figure illustrates a ratbrain because most of the neuroanatomical tracingstudies have been performed with rats. Presumably, thelocation and projections of acetylcholinergic neurons inthe human brain resemble those found in the rat brain,but we cannot yet be certain. The methods used for trac-ing particular systems of neurons in the brain and thedifficulty of doing such studies with the human brainare described in Chapter 5. (See Figure 4.9.)

Laterodorsal andpedunculopontinetegmental nuclei(dorsolateral pons)

Neocortex

Cingulatecortex

Olfactorybulb

Medialseptum

Caudate nucleus,putamen, andnucleus accumbens(contain interneurons)

Nucleusbasalis(basalforebrain)

AmygdalaLateralhypothalamus

Hippocampus

Medialhabenula

Thalamus

Substantianigra

PontinereticularformationRaphe

nuclei

Tectum

Deepcerebellarnuclei

LocuscoeruleusVestibular

nucleiMedullaryreticularformation

Dorsal

FIGURE 4.9 ■ Acetylcholinergic Pathways in a Rat Brain .

This schematic figure shows the locations of the most important groups of acetylcholinergicneurons and the distribution of their axons and terminal buttons.

(Adapted from Woolf, N. J. Progress in Neurobiology, 1991, 37, 475–524.)

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Acetylcholine is composed of two components:choline, a substance derived from the breakdown oflipids, and acetate, the anion found in vinegar, also calledacetic acid. Acetate cannot be attached directly tocholine; instead, it is transferred from a molecule ofacetyl-CoA. CoA (coenzyme A) is a complex molecule,consisting in part of the vitamin pantothenic acid (oneof the B vitamins). CoA is produced by the mitochon-dria, and it takes part in many reactions in the body.Acetyl-CoA is simply CoA with an acetate ion attached toit. ACh is produced by the following reaction: In thepresence of the enzyme choline acetyltransferase(ChAT), the acetate ion is transferred from the acetyl-CoA molecule to the choline molecule, yielding a mole-cule of ACh and one of ordinary CoA. (See Figure 4.10.)

A simple analogy will illustrate the role of coen-zymes in chemical reactions. Think of acetate as a hotdog and choline as a bun. The task of the person(enzyme) who operates the hot dog vending stand is toput a hot dog into the bun (make acetylcholine). To doso, the vendor needs a fork (coenzyme) to remove thehot dog from the boiling water. The vendor inserts thefork into the hot dog (attaches acetate to CoA) andtransfers the hot dog from fork to bun.

Two drugs, botulinum toxin and the venom of theblack widow spider, affect the release of acetylcholine.Botulinum toxin is produced by clostridium botulinum, abacterium that can grow in improperly canned food.This drug prevents the release of ACh (step 5 of Figure4.5). As we saw in this chapter’s opening case, botu-linum toxin drug is an extremely potent poison becausethe paralysis it can cause leads to suffocation. In con-trast, black widow spider venom has the opposite effect:It stimulates the release of ACh (step 4 of Figure 4.5).Although the effects of black widow spider venom canalso be fatal, the venom is much less toxic than botu-linum toxin. In fact, most healthy adults would have to

receive several bites, but infants or frail, elderly peoplewould be more susceptible.

You may have been wondering why double visionwas the first symptom of botulism in the opening case.The answer is that the delicate balance among the mus-cles that move the eyes is upset by any interference withacetylcholinergic transmission. You undoubtedly knowthat botox treatment has become fashionable. A verydilute (obviously!) solution of botulinum toxin is injectedinto people’s facial muscles to stop muscular contrac-tions that are causing wrinkles in the skin. I’m not plan-ning on getting a botox treatment, but if I did, I wouldwant to be sure that the solution was sufficiently dilute.

You will recall from Chapter 2 that after beingreleased by the terminal button, ACh is deactivated bythe enzyme acetylcholinesterase (AChE), which is pres-ent in the postsynaptic membrane. The deactivationproduces choline and acetate from ACh. Because theamount of choline that is picked up by the soma fromthe general circulation and then sent to the terminalbuttons by means of axoplasmic flow is not sufficient tokeep up with the loss of choline by an active synapse,choline must be recycled. After ACh is destroyed by theAChE in the postsynaptic membrane, the choline isreturned to the terminal buttons by means of reuptake.There, it is converted back into ACh. This process hasan efficiency of 50 percent; that is, half of the choline isretrieved and recycled. (See Figure 4.11.)

Reuptake of choline can be blocked by a drugcalled hemicholinium. Because this drug prevents therecycling of choline, the terminal button must rely solelyon transport of this substance from the cell body. Theresult is the production (and release) of less acetyl-choline, which means that hemicholinium serves as anacetylcholine antagonist. (See Figure 4.11.)

Drugs that deactivate AChE (step 11 of Figure 4.5)are used for several purposes. Some are used as insecti-cides. These drugs readily kill insects but not humans andother mammals, because our blood contains enzymes thatdestroy them. (Insects lack the enzyme.) Other AChEinhibitors are used medically. For example, a hereditarydisorder called myasthenia gravis is caused by an attack ofa person’s immune system against acetylcholine receptors

FIGURE 4.10 ■ Biosynthesis of Acetylcholine.

acetyl-CoA (a see tul ) A cofactor that supplies acetate for thesynthesis of acetylcholine.

choline acetyltransferase (ChAT) (koh leen a see tul trans fer ace)The enzyme that transfers the acetate ion from acetyl coenzyme Ato choline, producing the neurotransmitter acetylcholine.

botulinum toxin (bot you lin um) An acetylcholine antagonist;prevents release by terminal buttons.

black widow spider venom A poison produced by the blackwidow spider that triggers the release of acetylcholine.

hemicholinium (hem ee koh lin um) A drug that inhibits theuptake of choline.

Choline

Acetyl coenzyme A(acetyl-CoA)

Coenzyme A(CoA)

Acetylcholine (ACh)

ChAT transfersacetate ion fromacetyl-CoA tocholineCholine

acetyltransferase(ChAT)

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located on skeletal muscles. The person becomes weakerand weaker as the muscles become less responsive to theneurotransmitter. If the person is given an AChE inhibitorsuch as neostigmine, the person will regain some strengthbecause the acetylcholine that is released has a more pro-longed effect on the remaining receptors. (Neostigminecannot cross the blood–brain barrier, so it does not affectthe AChE found in the central nervous system.)

There are two types of ACh receptors: one ionotropicand one metabotropic. These receptors were identifiedwhen investigators discovered that different drugs acti-vated them (step 6 of Figure 4.5). The ionotropic AChreceptor is stimulated by nicotine, a drug found intobacco leaves. (The Latin name of the plant isNicotiniana tabacum.) The metabotropic ACh receptor isstimulated by muscarine, a drug found in the poisonmushroom Amanita muscaria. Consequently, these twoACh receptors are referred to as nicotinic receptors andmuscarinic receptors, respectively. Because musclefibers must be able to contract rapidly, they contain therapid, ionotropic nicotinic receptors.

Because muscarinic receptors are metabotropic innature and thus control ion channels through the

production of second messengers, their actions are slowerand more prolonged than those of nicotinic receptors.The central nervous system contains both kinds of AChreceptors, but muscarinic receptors predominate. Somenicotinic receptors are found at axoaxonic synapses inthe brain, where they produce presynaptic facilitation.Activation of these receptors is responsible for theaddictive effect of the nicotine found in tobacco smoke.

Just as two different drugs stimulate the two classesof acetylcholine receptors, two different drugs blockthem (step 7 of Figure 4.5). Both drugs were discoveredin nature long ago, and both are still used by modernmedicine. The first, atropine, blocks muscarinic recep-tors. The drug is named after Atropos, the Greek fatewho cut the thread of life (which a sufficient dose ofatropine will certainly do). Atropine is one of severalbelladonna alkaloids extracted from a plant called thedeadly nightshade, and therein lies a tale. Many yearsago, women who wanted to increase their attractivenessto men put drops containing belladonna alkaloids intotheir eyes. In fact, belladonna means “pretty lady.” Whywas the drug used this way? One of the unconsciousresponses that occurs when we are interested in some-thing is dilation of our pupils. By blocking the effects ofacetylcholine on the pupil, belladonna alkaloids such asatropine make the pupils dilate. This change makes awoman appear more interested in a man when she looksat him, and, of course, this apparent sign of interestmakes him regard her as more attractive.

Another drug, curare, blocks nicotinic receptors.Because these receptors are the ones found on muscles,curare, like botulinum toxin, causes paralysis. However,the effects of curare are much faster. The drug isextracted from several different species of plants foundin South America, where it was discovered long ago bypeople who used it to coat the tips of arrows and darts.Within minutes of being struck by one of these points,an animal collapses, ceases breathing, and dies.Nowadays, curare (and other drugs with the same site ofaction) are used to paralyze patients who are to under-go surgery so that their muscles will relax completelyand not contract when they are cut with a scalpel. Ananesthetic must also be used, because a person whoreceives only curare will remain perfectly conscious and

FIGURE 4.11 ■ The Acetycholine–Choline .Cycle .

The figure illustrates the destruction of acetylcholine byacetylcholinesterase and the reuptake of choline. The drughemicholinium blocks the reuptake of choline.

Recycled cholinemolecules

Presynaptic membrane

Choline transporter(can be inactivatedby hemicholinium)

Acetylcholinemolecule Acetate ion

Choline molecule

Action of AChEbreaks apartacetylcholinemolecule

Acetylcholin-esterase(AChE)

neostigmine (nee o stig meen) A drug that inhibits the activity ofacetylcholinesterase.

nicotinic receptor An ionotropic acetylcholine receptor that isstimulated by nicotine and blocked by curare.

muscarinic receptor (muss ka rin ic) A metabotropic acetylcholinereceptor that is stimulated by muscarine and blocked by atropine.

atropine (a tro peen) A drug that blocks muscarinic acetylcholinereceptors.

curare (kew rahr ee) A drug that blocks nicotinic acetylcholinereceptors.

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sensitive to pain, even though paralyzed. And, of course,a respirator must be used to supply air to the lungs.

The MonoaminesDopamine, norepinephrine, epinephrine, and serotoninare four chemicals that belong to a family of compoundscalled monoamines. Because the molecular structuresof these substances are similar, some drugs affect theactivity of all of them to some degree. The first three—dopamine, norepinephrine, and epinephrine—belongto a subclass of monoamines called catecholamines. It isworthwhile learning the terms in Table 4.1, because theywill be used many times throughout the rest of this book.(See Table 4.1.)

The monoamines are produced by several systemsof neurons in the brain. Most of these systems consist ofa relatively small number of cell bodies located in thebrain stem, whose axons branch repeatedly and give riseto an enormous number of terminal buttons distributedthroughout many regions of the brain. Monoaminergicneurons thus serve to modulate the function of wide-spread regions of the brain, increasing or decreasingthe activities of particular brain functions.

DopamineThe first catecholamine in Table 4.1, dopamine (DA),produces both excitatory and inhibitory postsynapticpotentials, depending on the postsynaptic receptor.Dopamine is one of the more interesting neurotransmit-ters because it has been implicated in several importantfunctions, including movement, attention, learning, andthe reinforcing effects of drugs that people tend to abuse;therefore, it is discussed in Chapters 8, 9, 13, and 18.

The synthesis of the catecholamines is somewhatmore complicated than that of ACh, but each step is asimple one. The precursor molecule is modified slightly,step by step, until it achieves its final shape. Each step iscontrolled by a different enzyme, which causes a smallpart to be added or taken off. The precursor for the twomajor catecholamine neurotransmitters (dopamine andnorepinephrine) is tyrosine, an essential amino acid thatwe must obtain from our diet. Tyrosine receives a

hydroxyl group (OH—an oxygen atom and a hydrogenatom) and becomes L-DOPA (L-3,4-dihydroxyphenylala-nine). The enzyme that adds the hydroxyl group iscalled tyrosine hydroxylase. L-DOPA then loses a carboxylgroup (COOH—one carbon atom, two oxygen atoms,and one hydrogen atom) through the activity of theenzyme DOPA decarboxylase and becomes dopamine.Finally, the enzyme dopamine -hydroxylase attaches ahydroxyl group to dopamine, which becomes norepi-nephrine. These reactions are shown in Figure 4.12.

b

TABLE 4.1 ■ Classification of the .Monoamine Neurotransmitters .

CATECHOLAMINES INDOLAMINES

Dopamine Serotonin

Norepinephrine

Epinephrine

FIGURE 4.12 ■ Biosynthesis of the .Catecholamines .

NH2

HO

H COOH

H H

NH2

L-DOPA

Tyrosinehydroxylase

DOPAdecarboxylase

Dopamine

C C

Tyrosine

Norepinephrine

Dopamine-hyroxylaseβ

HO

H COOH

H H

C C

HO

H

H H

NH2C C

HO H H

NH2C C

OH

OH

OH

H

OH H

monoamine (mahn o a meen) A class of amines that includesindolamines, such as serotonin; and catecholamines, such asdopamine, norepinephrine, and epinephrine.

catecholamine (cat a kohl a meen) A class of amines that includesthe neurotransmitters dopamine, norepinephrine, and epinephrine.

dopamine (DA) (dope a meen) A neurotransmitter; one of thecatecholamines.

L-DOPA (ell dope a) The levorotatory form of DOPA; theprecursor of the catecholamines; often used to treat Parkinson’sdisease because of its effect as a dopamine agonist.

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Neocortex

Hippocampus

Olfactorytubercle

Anteriorolfactorynucleus

Lateralseptum

Nucleusaccumbens

Amygdala

Globuspallidus

Caudate nucleusand putamenThalamus

Lateralhabenula

Ventraltegmentalarea

Substantianigra

Mesolimbic andMesocortical Systems

Nigrostriatal System

FIGURE 4.13 ■ Dopaminergic Pathways in a Rat Brain .

This schematic figure shows the locations of the most important groups of dopaminergicneurons and the distribution of their axons and terminal buttons.

(Adapted from Fuxe, K., Agnati, L. F., Kalia, M., Goldstein, M., Andersson K., and Harfstrand A. in Basic andClinical Aspects of Neuroscience: The Dopaminergic System, edited by E. Fluckinger, E. E. Muller, and M. O.Thomas. Berlin: Springer–Verlag, 1985.)

The brain contains several systems of dopaminergicneurons. The three most important of these originate inthe midbrain: in the substantia nigra and in the ventraltegmental area. (The substantia nigra was shown inFigure 3.23; the ventral tegmental area is located justbelow this region.) The cell bodies of neurons of thenigrostriatal system are located in the substantia nigraand project their axons to the neostriatum: the caudatenucleus and the putamen. The neostriatum is an impor-tant part of the basal ganglia, which is involved in thecontrol of movement. The cell bodies of neurons of themesolimbic system are located in the ventral tegmentalarea and project their axons to several parts of the lim-bic system, including the nucleus accumbens, amygdala,and hippocampus. The nucleus accumbens plays animportant role in the reinforcing (rewarding) effects ofcertain categories of stimuli, including those of drugsthat people abuse. The cell bodies of neurons of themesocortical system are also located in the ventraltegmental area. Their axons project to the prefrontalcortex. These neurons have an excitatory effect on thefrontal cortex and affect such functions as formation ofshort-term memories, planning, and strategy prepara-tion for problem solving. These three systems ofdopaminergic neurons are shown in Figure 4.13.

Degeneration of dopaminergic neurons that connectthe substantia nigra with the caudate nucleus causesParkinson’s disease, a movement disorder characterizedby tremors, rigidity of the limbs, poor balance, and

difficulty in initiating movements. The cell bodies ofthese neurons are located in a region of the brain calledthe substantia nigra (“black substance”). This region isnormally stained black with melanin, the substance thatgives color to skin. This compound is produced by thebreakdown of dopamine. (The brain damage thatcauses Parkinson’s disease was discovered by patholo-gists who observed that the substantia nigra of adeceased person who had had this disorder was pale ratherthan black.) People with Parkinson’s disease are givenL-DOPA, the precursor to dopamine. Although dopaminecannot cross the blood–brain barrier, L-DOPA can. OnceL-DOPA reaches the brain, it is taken up by dopaminergicneurons and is converted to dopamine (step 1 of Figure4.5). The increased synthesis of dopamine causes more

nigrostriatal system (nigh grow stry ay tul ) A system of neuronsoriginating in the substantia nigra and terminating in theneostriatum (caudate nucleus and putamen).

mesolimbic system (mee zo lim bik) A system of dopaminergicneurons originating in the ventral tegmental area and terminatingin the nucleus accumbens, amygdala, and hippocampus.

mesocortical system (mee zo kor ti kul ) A system of dopaminergicneurons originating in the ventral tegmental area and terminatingin the prefrontal cortex.

Parkinson’s disease A neurological disease characterized by tremors,rigidity of the limbs, poor balance, and difficulty in initiatingmovements; caused by degeneration of the nigrostriatal system.

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dopamine to be released by the surviving dopaminergicneurons in patients with Parkinson’s disease. As a conse-quence, the patients’ symptoms are alleviated.

Another drug, AMPT (or -methyl-p-tyrosine), inac-tivates tyrosine hydroxylase, the enzyme that convertstyrosine to L-DOPA (step 2 of Figure 4.5). Because thisdrug interferes with the synthesis of dopamine (and ofnorepinephrine as well), it serves as a catecholamineantagonist. The drug is not normally used medically, butit has been used as a research tool in laboratory animals.

The drug reserpine prevents the storage ofmonoamines in synaptic vesicles by blocking the trans-porters in the membrane of vesicles of monoaminergicneurons (step 3 of Figure 4.5). Because the synaptic vesi-cles remain empty, no neurotransmitter is releasedwhen an action potential reaches the terminal button.Reserpine, then, is a monoamine antagonist. The drug,which comes from the root of a shrub, was discoveredover 3000 years ago in India, where it was found to beuseful in treating snakebite and seemed to have a calm-ing effect. Pieces of the root are still sold in markets inrural areas of India. In Western medicine, reserpine waspreviously used to treat high blood pressure, but it hasbeen replaced by drugs with fewer side effects.

Several different types of dopamine receptors havebeen identified, all metabotropic. Of these, two are themost common: receptors and receptors. It appears that

receptors are exclusively postsynaptic, whereas receptors are found both presynaptically and postsynap-tically in the brain. Stimulation of receptors increasesthe production of the second messenger cyclic AMP,

D1

D2D1

D2D1

a

whereas stimulation of receptors decreases it, as doesstimulation of and receptors. Several drugs stimu-late or block specific types of dopamine receptors.

Autoreceptors are found in the dendrites, soma,and terminal buttons of dopaminergic neurons.Activation of the autoreceptors in the dendritic andsomatic membrane decreases neural firing by produc-ing hyperpolarizations. The presynaptic autoreceptorslocated in the terminal buttons suppress the activity ofthe enzyme tyrosine hydroxylase and thus decrease theproduction of dopamine—and ultimately its release.Dopamine autoreceptors resemble receptors, butthere seem to be some differences. For example, thedrug apomorphine is a agonist, but it seems to havea greater affinity for presynaptic receptors than forpostsynaptic receptors. A low dose of apomorphineacts as an antagonist, because it stimulates the presynap-tic receptors and inhibits the production and release ofdopamine. Higher doses begin to stimulate postsynaptic

receptors, and the drug begins to act as a direct ago-nist. (See Figure 4.14.)D2

D2

D2

D2

D2

D4D3

D2

Presynaptic autoreceptorshave high affinity forapomorphine; even at lowdoses many are activated;acts as an antagonist

Terminalbutton

Inhibition ofdopamine production

Inhibition ofdopamine production

Postsynapticmembrane

At high doses,apomorphine bindswith postsynapticreceptors; acts asan agonist

FIGURE 4.14 ■ Effects of Low and High Doses of Apomorphine .

At low doses, apomorphine serves as a dopamine antagonist; at high doses, it serves as an agonist.

AMPT A drug that blocks the activity of tyrosine hydroxylase andthus interferes with the synthesis of the catecholamines.

reserpine (ree sur peen) A drug that interferes with the storage ofmonoamines in synaptic vesicles.

apomorphine (ap o more feen) A drug that blocks dopamineautoreceptors at low doses; at higher doses, blocks postsynapticreceptors as well.

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Several drugs inhibit the reuptake of dopamine,thus serving as potent dopamine agonists (step 10 ofFigure 4.5). The best known of these drugs are amphet-amine, cocaine, and methylphenidate. Amphetaminehas an interesting effect: It causes the release of bothdopamine and norepinephrine by causing the trans-porters for these neurotransmitters to run in reverse,propelling DA and NE into the synaptic cleft. Of course,this action also blocks reuptake of these neurotransmit-ters. Cocaine and methylphenidate simply blockdopamine reuptake. Because cocaine also blocks voltage-dependent sodium channels, it is sometimes used as atopical anesthetic, especially in the form of eye drops foreye surgery. Methylphenidate (Ritalin) is used to treatchildren who have attention deficit disorder.

The production of the catecholamines is regulatedby an enzyme called monoamine oxidase (MAO). Thisenzyme is found within monoaminergic terminal but-tons, where it destroys excessive amounts of neurotrans-mitter. A drug called deprenyl destroys the particularform of monoamine oxidase (MAO-B) that is found indopaminergic terminal buttons. Because deprenyl pre-vents the destruction of dopamine, more dopamine isreleased when an action potential reaches the terminalbutton. Thus, deprenyl serves as a dopamine agonist.(See Figure 4.15.)

MAO is also found in the blood, where it deactivatesamines that are present in foods such as chocolate andcheese. Without such deactivation these amines couldcause dangerous increases in blood pressure.

Dopamine has been implicated as a neurotransmit-ter that might be involved in schizophrenia, a seriousmental disorder whose symptoms include hallucina-tions, delusions, and disruption of normal, logicalthought processes. Drugs such as chlorpromazine,

which block receptors, alleviate these symptoms(step 7 of Figure 4.5). Hence, investigators have specu-lated that schizophrenia is produced by overactivity ofdopaminergic neurons. More recently discovereddrugs—the so-called atypical antipsychotics—have morecomplicated actions, which are discussed in Chapter 16.

NorepinephrineBecause norepinephrine (NE), like ACh, is found inneurons in the autonomic nervous system, this neuro-transmitter has received much experimental attention. Ishould note that the terms Adrenalin and epinephrine aresynonymous, as are noradrenalin and norepinephrine. Letme explain why. Epinephrine is a hormone produced bythe adrenal medulla, the central core of the adrenalglands, located just above the kidneys. Epinephrinealso serves as a neurotransmitter in the brain, but it isof minor importance compared with norepinephrine.

D2

MAO convertsdopamine toan inactivesubstance

Dopamine

Dopamine is storedin synaptic vesicles

MAO MAOInactivesubstance

Because of the higherconcentration of dopamine,more dopamine is storedin synaptic vesicles

Deprenyl, an MAOinhibitor, blocks thedestruction of dopamine

FIGURE 4.15 ■ Role of Monoamine Oxidase .

This schematic shows the role of monoamine oxidase in dopaminergic terminal buttonsand the action of deprenyl.

methylphenidate (meth ul fen i date) A drug that inhibits thereuptake of dopamine.

monoamine oxidase (MAO) (mahn o a meen) A class of enzymesthat destroy the monoamines: dopamine, norepinephrine, andserotonin.

deprenyl (depp ra nil ) A drug that blocks the activity of MAO-B;acts as a dopamine agonist.

chlorpromazine (klor proh ma zeen) A drug that reduces thesymptoms of schizophrenia by blocking dopamine receptors.

norepinephrine (NE) (nor epp i neff rin) One of thecatecholamines; a neurotransmitter found in the brain and in thesympathetic division of the autonomic nervous system.

epinephrine (epp i neff rin) One of the catecholamines; ahormone secreted by the adrenal medulla; serves also as aneurotransmitter in the brain.

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Ad renal is Latin for “toward the kidney.” In Greek, onewould say epi nephron (“upon the kidney”), hence theterm epinephrine. The latter term has been adopted bypharmacologists, probably because the word Adrenalinwas appropriated by a drug company as a proprietaryname; therefore, to be consistent with general usage, Iwill refer to the neurotransmitter as norepinephrine. Theaccepted adjectival form is noradrenergic; I suppose thatnorepinephrinergic never caught on because it takes solong to pronounce.

We have already seen the biosynthetic pathway fornorepinephrine in Figure 4.12. The drug AMPT, whichprevents the conversion of tyrosine to L-DOPA, blocksthe production of norepinephrine as well as dopamine(step 2 of Figure 4.5).

Most neurotransmitters are synthesized in the cyto-plasm of the terminal button and then stored in newlyformed synaptic vesicles. However, for norepinephrinethe final step of synthesis occurs inside the vesicles them-selves. The vesicles are first filled with dopamine. Thenthe dopamine is converted to norepinephrine throughthe action of the enzyme dopamine -hydroxylase locatedwithin the vesicles. The drug fusaric acid inhibits theactivity of the enzyme dopamine- -hydroxylase and thusblocks the production of norepinephrine without affect-ing the production of dopamine.

Excess norepinephrine in the terminal buttons isdestroyed by monoamine oxidase, type A. The drugmoclobemide specifically blocks MAO-A and henceserves as a noradrenergic agonist.

Almost every region of the brain receives inputfrom noradrenergic neurons. The cell bodies of most ofthese neurons are located in seven regions of the pons

b

b

and medulla and one region of the thalamus. The cellbodies of the most important noradrenergic systembegin in the locus coeruleus, a nucleus located in thedorsal pons. The axons of these neurons project to theregions shown in Figure 4.16. As we will see later, the pri-mary effect of activation of these neurons is an increasein vigilance—attentiveness to events in the environ-ment. (See Figure 4.16.)

Most neurons that release norepinephrine do notdo so through terminal buttons on the ends of axonalbranches. Instead, they usually release them throughaxonal varicosities, beadlike swellings of the axonalbranches. These varicosities give the axonal branches ofcatecholaminergic neurons the appearance of beadedchains.

There are several types of noradrenergic receptors,identified by their differing sensitivities to various drugs.Actually, these receptors are usually called adrenergicreceptors rather than noradrenergic receptors, becausethey are sensitive to epinephrine (Adrenalin) as well asnorepinephrine. Neurons in the central nervous system

Neocortex

Hippocampus

Amygdala

Thalamus

Olfactorybulb

Tectum

Locuscoeruleus

Septum

Preopticarea

Hypothalamus

Basalganglia

Dorsal bundle

Cerebellum

Spinalcord

Ventral bundle

FIGURE 4.16 ■ Noradrenergic Pathways in a Rat Brain .

This schematic figure shows the locations of the most important groups of noradrenergicneurons and the distribution of their axons and terminal buttons.

(Adapted from Cotman, C. W. and McGaugh, J. L. Behavioral Neuroscience: An Introduction. New York: AcademicPress, 1980.)

fusaric acid ( few sahr ik) A drug that inhibits the activity of theenzyme dopamine- -hydroxylase and thus blocks the productionof norepinephrine.

moclobemide (mok low bem ide) A drug that blocks the activity ofMAO-A; acts as a noradrenergic agonist.

locus coeruleus (sur oo lee us) A dark-colored group ofnoradrenergic cell bodies located in the pons near the rostral end ofthe floor of the fourth ventricle.

axonal varicosity An enlarged region along the length of an axonthat contains synaptic vesicles and releases a neurotransmitter orneuromodulator.

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contain - and -adrenergic receptors and - and -adrenergic receptors. All four kinds of receptors are alsofound in various organs of the body besides the brain andare responsible for the effects of epinephrine and norep-inephrine when they act as hormones outside the centralnervous system. In the brain, all autoreceptors appear tobe of the type. (The drug idazoxan blocks auto-receptors and hence acts as an agonist.) All adrenergicreceptors are metabotropic, coupled to G proteins thatcontrol the production of second messengers.

Adrenergic receptors produce both excitatory andinhibitory effects. In general, the behavioral effects of therelease of NE are excitatory. In the brain, receptorsproduce a slow depolarizing (excitatory) effect on thepostsynaptic membrane, while receptors produce aslow hyperpolarization. Both types of receptorsincrease the responsiveness of the postsynaptic neuronto its excitatory inputs, which presumably related to therole this neurotransmitter plays in vigilance.Noradrenergic neurons—in particular, receptors—are also involved in sexual behavior and in the controlof appetite.

SerotoninThe third monoamine neurotransmitter, serotonin (alsocalled 5-HT, or 5-hydroxytryptamine), has also receivedmuch experimental attention. Its behavioral effects arecomplex. Serotonin plays a role in the regulation ofmood; in the control of eating, sleep, and arousal; andin the regulation of pain. Serotonergic neurons areinvolved somehow in the control of dreaming.

The precursor for serotonin is the amino acidtryptophan. The enzyme tryptophan hydroxylase adds ahydroxyl group, producing 5-HTP (5-hydroxytryptophan).The enzyme 5-HTP decarboxylase removes a carboxylgroup from 5-HTP, and the result is 5-HT (serotonin).(See Figure 4.17.) The drug PCPA (p-chlorophenylala-nine) blocks the activity of tryptophan hydroxylase andthus serves as a serotonergic antagonist.

The cell bodies of serotonergic neurons are foundin nine clusters, most of which are located in the raphenuclei of the midbrain, pons, and medulla. Like norep-inephrine, 5-HT is released from varicosities rather thanterminal buttons. The two most important clusters ofserotonergic cell bodies are found in the dorsal andmedial raphe nuclei, and I will restrict my discussion tothese clusters. The word raphe means “seam” or “crease”and refers to the fact that most of the raphe nuclei arefound at or near the midline of the brain stem. Both thedorsal and median raphe nuclei project axons to thecerebral cortex. In addition, neurons in the dorsalraphe innervate the basal ganglia, and those in themedian raphe innervate the dentate gyrus, a part of thehippocampal formation. These and other connectionsare shown in Figure 4.18.

a2

b

a2

a1

a2a2

a2a1b2b1

Investigators have identified at least nine differenttypes of serotonin receptors: ,

, and . Of these the and receptors serve as presynaptic autoreceptors. In the dor-sal and median raphe nuclei, receptors serve asautoreceptors in the membrane of dendrites and soma.All 5-HT receptors are metabotropic except for the

receptor, which is ionotropic. The receptorcontrols a chloride channel, which means that it pro-duces inhibitory postsynaptic potentials. These recep-tors appear to play a role in nausea and vomiting,because antagonists have been found to be usefulin treating the side effects of chemotherapy and radio-therapy for the treatment of cancer. Pharmacologistshave discovered drugs that serve as agonists or antago-nists for some, but not all, of the types of 5-HT receptors.

Drugs that inhibit the reuptake of serotonin havefound a very important place in the treatment of men-tal disorders. The best known of these, fluoxetine(Prozac), is used to treat depression, some forms of

5-HT3

5-HT35-HT3

5-HT1A

5-HT1D5-HT1B5-HT35-HT2A–2C

5-HT1D–1F5-HT1A–1B

FIGURE 4.17 ■ Biosynthesis of Serotonin .(5-Hydroxytryptamine, or 5-HT) .

N

CH2 CH NH2

COOH

N

CH2 CH NH2

COOH

N

CH2 NH2

Tryptophan

HO

5-hydroxytryptophan(5-HTP)

CH2HO

5-hydroxytryptamine(5-HT, or serotonin)

Tryptophanhydroxylase

5-HTPdecarboxylase

idazoxan A drug that blocks presynaptic noradrenergic receptors and hence acts as an agonist, facilitating the synthesis andrelease of NE.

serotonin (5-HT) (sair a toe nin) An indolamine neurotransmitter;also called 5-hydroxytryptamine.

PCPA A drug that inhibits the activity of tryptophan hydroxylaseand thus interferes with the synthesis of 5-HT.

fluoxetine ( floo ox i teen) A drug that inhibits the reuptake of 5-HT.

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anxiety disorders, and obsessive-compulsive disorder.These disorders—and their treatment—are discussed inChapters 16 and 17. Another drug, fenfluramine, whichcauses the release of serotonin as well as inhibits itsreuptake, has been used as an appetite suppressant inthe treatment of obesity. Chapter 12 discusses the topicof obesity and its control by means of drugs.

Several hallucinogenic drugs produce their effectsby interacting with serotonergic transmission. LSD(lysergic acid diethylamide) produces distortions ofvisual perceptions that some people find awesome andfascinating but that simply frighten other people. Thisdrug, which is effective in extremely small doses, is adirect agonist for postsynaptic receptors in theforebrain. Another drug, MDMA (methylenedioxy-methamphetamine), is both a noradrenergic and a sero-tonergic agonist and has both excitatory and hallucino-genic effects. Like its relative amphetamine, MDMA(popularly called “ecstasy”) causes noradrenergic trans-porters to run backwards, this causing the release of NEand inhibiting its reuptake. This site of action is appar-ently responsible for the drug’s excitatory effect. MDMAalso causes serotonergic transporters to run backwards,and this site of action is apparently responsible for thedrug’s hallucinogenic effects. Unfortunately, researchindicates that MDMA can damage serotonergic neuronsand cause cognitive deficits.

Amino AcidsSo far, all of the neurotransmitters I have described aresynthesized within neurons: acetylcholine from choline,the catecholamines from the amino acid tyrosine, and

5-HT2A

serotonin from the amino acid tryptophan. Some neu-rons secrete simple amino acids as neurotransmitters.Because amino acids are used for protein synthesis by allcells of the brain, it is difficult to prove that a particularamino acid is a neurotransmitter. However, investigatorssuspect that at least eight amino acids may serve as neu-rotransmitters in the mammalian central nervous sys-tem. As we saw in the introduction to this section, threeof them are especially important because they are themost common neurotransmitters in the CNS: gluta-mate, gamma-aminobutyric acid (GABA), and glycine.

GlutamateBecause glutamate (also called glutamic acid) and GABAare found in very simple organisms, many investigatorsbelieve that these neurotransmitters were the first tohave evolved. Besides producing postsynaptic potentialsby activating postsynaptic receptors, they also havedirect excitatory effects (glutamic acid) and inhibitoryeffects (GABA) on axons; they raise or lower the thresh-old of excitation, thus affecting the rate at which actionpotentials occur. These direct effects suggest that thesesubstances had a general modulating role even before

Neocortex

Hippocampus

Amygdala

Thalamus

Olfactorybulb

Tectum

Septum

Hypothalamus

Basalganglia

Cerebellum

Spinalcord

Olfactorytubercle

Substantianigra

Raphenuclei

Habenula

Spinaltrigeminal nucleus

FIGURE 4.18 ■ Serotonergic Pathways in a Rat Brain .

This schematic figure shows the locations of the most important groups of serotonergicneurons and the distribution of their axons and terminal buttons.

(Adapted from Consolazione, A. and Cuello, A. C. CNS serotonin pathways. In Biology of SerotonergicTransmission, edited by N. N. Osborne. Chichester: England: Wiley & Sons, 1982.)

fenfluramine ( fen fluor i meen) A drug that stimulates the releaseof 5-HT.

LSD A drug that stimulates receptors.

MDMA A drug that serves as a noradrenergic and serotonergicagonist, also known as “ecstasy”; has excitatory and hallucinogeniceffects.

glutamate An amino acid; the most important excitatoryneurotransmitter in the brain.

5-HT2A

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the evolutionary development of specific receptormolecules.

Glutamate is the principal excitatory neurotransmit-ter in the brain and spinal cord. It is produced in abun-dance by the cells’ metabolic processes. There is noeffective way to prevent its synthesis without disruptingother activities of the cell.

Investigators have discovered four major types ofglutamate receptors. Three of these receptors areionotropic and are named after the artificial ligands thatstimulate them: the NMDA receptor, the AMPA recep-tor, and the kainate receptor. The other glutamatereceptor—the metabotropic glutamate receptor—is(obviously!) metabotropic. Actually, there appear to beat least eight subtypes of metabotropic glutamate recep-tors, but little is known about their functions except thatsome of them serve as presynaptic autoreceptors. TheAMPA receptor is the most common glutamate recep-tor. It controls a sodium channel, so when glutamateattaches to the binding site, it produces EPSPs. Thekainate receptor has similar effects.

The NMDA receptor has some special—and veryimportant—characteristics. It contains at least six differ-ent binding sites: four located on the exterior of thereceptor and two located deep within the ion channel.When it is open, the ion channel controlled by theNMDA receptor permits both sodium and calcium ionsto enter the cell. The influx of both of these ions causesa depolarization, of course, but the entry of calcium( ) is especially important. Calcium serves as a sec-ond messenger, binding with—and activating—variousenzymes within the cell. These enzymes have profoundeffects on the biochemical and structural properties ofthe cell. As we shall see, one important result is alter-ation in the characteristics of the synapse that provideone of the building blocks of a newly formed memory.These effects of NMDA receptors will be discussed inmuch more detail in Chapter 13. The drug AP5 (2-amino-5-phosphonopentanoate) blocks the glutamatebinding site on the NMDA receptor and impairs synap-tic plasticity and certain forms of learning.

Figure 4.19 presents a schematic diagram of anNMDA receptor and its binding sites. Obviously, gluta-mate binds with one of these sites, or we would not callit a glutamate receptor. However, glutamate by itself can-not open the calcium channel. For that to happen, amolecule of glycine must be attached to the glycinebinding site, located on the outside of the receptor. (Wedo not yet understand why glycine—which also serves asan inhibitory neurotransmitter in some parts of the cen-tral nervous system—is required for this ion channel toopen.) (See Figure 4.19.)

An additional requirement for the opening of thecalcium channel is that a magnesium ion not beattached to the magnesium binding site, located deepwithin the channel. Under normal conditions, when the

Ca2+

postsynaptic membrane is at the resting potential, amagnesium ion ( ) is attracted to the magnesiumbinding site and blocks the calcium channel. If a mole-cule of glutamate attaches to its binding site, the chan-nel widens, but the magnesium ion still blocks it, so nocalcium can enter the postsynaptic neuron. However, ifthe postsynaptic membrane is partially depolarized, themagnesium ion is repelled from its binding site. Thus,the NMDA receptor opens only if glutamate is presentand the postsynaptic membrane is depolarized. TheNMDA receptor, then, is a voltage- and neurotransmit-ter-dependent ion channel. (See Figure 4.19.)

What about the other three binding sites? If a zincion ( ) binds with the zinc binding site, the activityof the NMDA receptor is decreased. On the other hand,the polyamine site has a facilitatory effect. (Polyaminesare chemicals that have been shown to be important for

Zn2+

Mg2+

FIGURE 4.19 ■ NMDA Receptor .

This schematic illustration of an NMDA receptor shows itsbinding sites.

Glycine

PCPMg2+

Zn2+Calciumchannel

GlutamatePolyamine

++

NMDA receptor A specialized ionotropic glutamate receptor thatcontrols a calcium channel that is normally blocked by ions;has several other binding sites.

AMPA receptor An ionotropic glutamate receptor that controls asodium channel; stimulated by AMPA.

kainate receptor (kay in ate) An ionotropic glutamate receptorthat controls a sodium channel; stimulated by kainic acid.

metabotropic glutamate receptor (meh tab a troh pik) A categoryof metabotropic receptors that are sensitive to glutamate.

AP5 (2-amino-5-phosphonopentanoate) A drug that blocks theglutamate binding site on NMDA receptors.

Mg2+

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tissue growth and development. The significance of thepolyamine binding site is not yet understood.) The PCPsite, located deep within the ion channel near the mag-nesium binding site, binds with a hallucinogenic drug,PCP (phencyclidine, also known as “angel dust”). PCPserves as an indirect antagonist; when it attaches to itsbinding site, calcium ions cannot pass through the ionchannel. PCP is a synthetic drug and is not produced bythe brain. Thus, it is not the natural ligand of the PCPbinding site. What that ligand is and what useful func-tions it serves are not yet known. The behavioral symp-toms of PCP are listed in Table 4.2.

Several drugs affect glutamatergic synapses. As youalready know, NMDA, AMPA, and kainate (more precisely,kainic acid) serve as direct agonists at the receptorsnamed after them. In addition, one of the most commondrugs—alcohol—serves as an antagonist of NMDAreceptors. As we will see in Chapter 19, this effect isresponsible for the seizures that can be provoked by sud-den withdrawal from heavy long-term alcohol intake.

GABAGABA (gamma-aminobutyric acid) is produced fromglutamic acid by the action of an enzyme (glutamic aciddecarboxylase, or GAD) that removes a carboxyl group.The drug allylglycine inactivates GAD and thus preventsthe synthesis of GABA (step 2 of Figure 4.5). GABA is aninhibitory neurotransmitter, and it appears to have awidespread distribution throughout the brain andspinal cord. Two GABA receptors have been identified:

and . The receptor is ionotropicand controls a chloride channel; the receptor ismetabotropic and controls a potassium channel.

GABAB

GABAAGABABGABAA

As you know, neurons in the brain are greatly inter-connected. Without the activity of inhibitory synapsesthese interconnections would make the brain unstable.That is, through excitatory synapses neurons wouldexcite their neighbors, which would then excite theirneighbors, which would then excite the originally activeneurons, and so on, until most of the neurons in thebrain would be firing uncontrollably. In fact, this eventdoes sometimes occur, and we refer to it as a seizure.(Epilepsy is a neurological disorder characterized by thepresence of seizures.) Normally, an inhibitory influenceis supplied by GABA-secreting neurons, which are pres-ent in large numbers in the brain. Some investigatorsbelieve that one of the causes of epilepsy is an abnormal-ity in the biochemistry of GABA-secreting neurons or inGABA receptors.

Like NMDA receptors, receptors are com-plex; they contain at least five different binding sites.The primary binding site is, of course, for GABA. Thedrug muscimol (derived from the ACh agonist mus-carine) serves as a direct agonist for this site (step 6 ofFigure 4.5). Another drug, bicuculline, blocks thisGABA binding site, serving as a direct antagonist (step 7of Figure 4.5). A second site on the receptorbinds with a class of tranquilizing drugs called thebenzodiazepines. These drugs include diazepam(Valium) and chlordiazepoxide (Librium), which areused to reduce anxiety, promote sleep, reduce seizureactivity, and produce muscle relaxation. The third sitebinds with barbiturates. The fourth site binds with vari-ous steroids, including some steroids used to producegeneral anesthesia. The fifth site binds with picrotoxin,a poison found in an East Indian shrub. In addition,alcohol binds with one of these sites—probably the ben-zodiazepine binding site. (See Figure 4.20.)

Barbiturates, drugs that bind to the steroid site, andbenzodiazepines all promote the activity of the receptor; thus, all these drugs serve as indirect agonists.The benzodiazepines are very effective anxiolytics, or

GABAA

GABAA

GABAA

TABLE 4.2 ■ Behavioral Symptoms of .Phencyclidine (PCP) .

Altered body image

Feelings of isolation and aloneness

Cognitive disorganization

Drowsiness and apathy

Negativism and hostility

Feelings of euphoria and inebriation

Dreamlike states

Adapted from Feldman, Meyer, and Quenzer, 1997.

PCP Phencyclidine; a drug that binds with the PCP binding siteof the NMDA receptor and serves as an indirect antagonist.

GABA An amino acid; the most important inhibitoryneurotransmitter in the brain.

allylglycine A drug that inhibits the activity of GAD and thusblocks the synthesis of GABA.

muscimol (musk i mawl ) A direct agonist for the GABA bindingsite on the receptor.

bicuculline (by kew kew leen) A direct antagonist for the GABAbinding site on the receptor.

benzodiazepine (ben zoe dy azz a peen) A category of anxiolyticdrugs; an indirect agonist for the receptor.

anxiolytic (angz ee oh lit ik) An anxiety-reducing effect.

GABAA

GABAA

GABAA

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“anxiety-dissolving” drugs. They are often used to treatpeople with anxiety disorders. In addition, some benzo-diazepines serve as effective sleep medications, and oth-ers are used to treat some types of seizure disorder.

In low doses, barbiturates have a calming effect. Inprogressively higher doses they produce difficulty inwalking and talking, unconsciousness, coma, and death.Although veterinarians sometimes use barbiturates toproduce anesthesia for surgery, the therapeutic index—the ratio between a dose that produces anesthesia andone that causes fatal depression of the respiratory cen-ters of the brain—is small. As a consequence, thesedrugs are rarely used by themselves to produce surgicalanesthesia in humans.

Picrotoxin has effects opposite to those of benzodi-azepines and barbiturates: It inhibits the activity of the

receptor, thus serving as an indirect antagonist.In high enough doses, this drug causes convulsions.

Various steroid hormones are normally produced inthe body, and some hormones related to progesterone(the principal pregnancy hormone) act on the steroidbinding site of the receptor, producing a relax-ing, anxiolytic sedative effect. However, the brain doesnot produce Valium, barbiturates, or picrotoxin. Whatare the natural ligands for these binding sites? So far,most research has concentrated on the benzodiazepinebinding site. These binding sites are more complex thanthe others. They can be activated by drugs such as thebenzodiazepines, which promote the activity of thereceptor and thus serve as indirect agonists. They can

GABAA

GABAA

also be activated by other drugs that have the oppositeeffect—that inhibit the activity of the receptor, thus serv-ing as indirect antagonists. Presumably, the brain pro-duces natural ligands that act as indirect agonists orantagonists at the benzodiazepine binding site, but sofar, such a chemical has not been identified.

What about the receptor? This metabotropicreceptor, coupled to a G protein, serves as both a post-synaptic receptor and a presynaptic autoreceptor. A

agonist, baclofen, serves as a muscle relaxant.Another drug, CGP 335348, serves as an antagonist. Theactivation of receptors opens potassium chan-nels, producing hyperpolarizing inhibitory postsynapticpotentials.

GlycineThe amino acid glycine appears to be the inhibitoryneurotransmitter in the spinal cord and lower portionsof the brain. Little is known about its biosynthetic path-way; there are several possible routes, but not enough isknown to decide how neurons produce glycine. Thebacteria that cause tetanus (lockjaw) release a chemicalthat prevents the release of glycine (and GABA as well);the removal of the inhibitory effect of these synapsescauses muscles to contract continuously.

The glycine receptor is ionotropic, and it controls achloride channel. Thus, when it is active, it producesinhibitory postsynaptic potentials. The drug strychnine,an alkaloid found in the seeds of the Strychnos nux vom-ica, a tree found in India, serves as a glycine antagonist.Strychnine is very toxic, and even relatively small dosescause convulsions and death. No drugs have yet beenfound that serve as specific glycine agonists.

Researchers have discovered that some terminal but-tons in the brain release both glycine and GABA (Jonas,Bischofberger, and Sandkühler, 1998; Nicoll andMalenka, 1998). The apparent advantage for the co-release of these two inhibitory neurotransmitters is theproduction of rapid, long-lasting postsynaptic potentials:The glycine stimulates rapid ionotropic receptors, andthe GABA stimulates long-lasting metabotropic recep-tors. Obviously, the postsynaptic membrane at thesesynapses contains both glycine and GABA receptors.

PeptidesRecent studies have discovered that the neurons of thecentral nervous system release a large variety of pep-tides. Peptides consist of two or more amino acidslinked together by peptide bonds. All the peptides that

GABAB

GABAB

GABAB

FIGURE 4.20 ■ GABAA Receptor .

This schematic illustration of a GABAA receptor shows itsbinding sites.

Barbiturate(and alcohol?)site

Picrotoxinsite

GABA site Chloridechannel

Steroidsite

Benzodiazepinesite

++

––

glycine (gly seen) An amino acid; an important inhibitoryneurotransmitter in the lower brain stem and spinal cord.

strychnine (strik neen) A direct antagonist for the glycine receptor.

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have been studied so far are produced from precursormolecules. These precursors are large polypeptides thatare broken into pieces by special enzymes. Neuronsmanufacture both the polypeptides and the enzymesneeded to break them apart in the right places. Theappropriate sections of the polypeptides are retained,and the rest are destroyed. Because the synthesis of pep-tides takes place in the soma, vesicles containing thesechemicals must be delivered to the terminal buttons byaxoplasmic transport.

Peptides are released from all parts of the terminalbutton, not just from the active zone; thus, only a por-tion of the molecules are released into the synaptic cleft.The rest presumably act on receptors belonging toother cells in the vicinity. Once released, peptides aredestroyed by enzymes. There is no mechanism for reup-take and recycling of peptides.

Several different peptides are released by neurons.Although most peptides appear to serve as neuromodu-lators, some act as neurotransmitters. One of the bestknown families of peptides is the endogenous opioids.(Endogenous means “produced from within”; opioidmeans “like opium.”) Several years ago it became clearthat opiates (drugs such as opium, morphine, and heroin)reduce pain because they have direct effects on thebrain. (Please note that the term opioid refers to endoge-nous chemicals, and opiate refers to drugs.) Pert,Snowman, and Snyder (1974) discovered that neuronsin a localized region of the brain contain specializedreceptors that respond to opiates. Then, soon after thediscovery of the opiate receptor, other neuroscientistsdiscovered the natural ligands for these receptors(Terenius and Wahlström, 1975; Hughes et al., 1975),which they called enkephalins (from the Greek wordenkephalos, “in the head”). We now know that theenkephalins are only two members of a family of endoge-nous opioids, all of which are synthesized from one ofthree large peptides that serve as precursors. In addition,we know that there are at least three different types ofopiate receptors: (mu), (delta), and (kappa).

Several different neural systems are activated whenopiate receptors are stimulated. One type producesanalgesia, another inhibits species-typical defensiveresponses such as fleeing and hiding, and another stim-ulates a system of neurons involved in reinforcement(“reward”). The last effect explains why opiates areoften abused. The situations that cause neurons tosecrete endogenous opioids are discussed in Chapter 7,and the brain mechanisms of opiate addiction are dis-cussed in Chapter 18.

So far, pharmacologists have developed only two typesof drugs that affect neural communication by means ofopioids: direct agonists and antagonists. Many syntheticopiates, including heroin (dihydromorphine) andPercodan (levorphanol), have been developed, and someare used clinically as analgesics (step 6 of Figure 4.5).

kdm

Several opiate receptors blockers have also been devel-oped (step 7 of Figure 4.5). One of them, naloxone, isused clinically to reverse opiate intoxication. This drughas saved the lives of many drug abusers who would other-wise have died of an overdose of heroin.

As we saw in Chapter 2, many terminal buttons con-tain two different types of synaptic vesicles, each filledwith a different substance. These terminal buttons releasepeptides in conjunction with a “classical” neurotransmit-ter (one of those I just described). One reason for thecorelease of peptides is their ability to regulate the sensi-tivity of presynaptic or postsynaptic receptors to the neu-rotransmitter. For example, the terminal buttons of thesalivary nerve of the cat (which control the secretion ofsaliva) release both acetylcholine and a peptide calledVIP. When the axons fire at a low rate, only ACh isreleased and only a little saliva is secreted. At a higherrate, both ACh and VIP are secreted, and the VIP dramat-ically increases the sensitivity of the muscarinic receptorsin the salivary gland to ACh; thus, much saliva is released.

Several peptide hormones released by endocrineglands are also found in the brain, where they serve asneuromodulators. In some cases the peripheral andcentral peptides perform related functions. For exam-ple, outside the nervous system the hormone an-giotensin acts directly on the kidneys and blood vesselsto produce effects that help the body cope with the lossof fluid, and inside the nervous system circuits of neu-rons that use angiotensin as a neurotransmitter performcomplementary functions, including the activation ofneural circuits that produce thirst. The existence of theblood–brain barrier keeps hormones in the general cir-culation separate from the extracellular fluid in thebrain, which means that the same peptide molecule canhave different effects in these two regions.

Many peptides produced in the brain have interest-ing behavioral effects, which will be discussed in subse-quent chapters.

LipidsVarious substances derived from lipids can serve totransmit messages within or between cells. The bestknown, and probably the most important, are the twoendocannabinoids (“endogenous cannabis-like sub-stances”)—natural ligands for the receptors that are

endogenous opioid (en dodge en us oh pee oyd ) A class of peptidessecreted by the brain that act as opiates.

enkephalin (en keff a lin) One of the endogenous opioids.

naloxone (na lox own) A drug that blocks opiate receptors.

endocannabinoid (en do can ab in oid ) A lipid; an endogenousligand for cannabinoid receptors, which also bind with THC, theactive ingredient of marijuana.

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responsible for the physiological effects of the activeingredient in marijuana. Matsuda et al. (1990) discov-ered that THC (tetrahydrocannabinol, the active ingre-dient of marijuana) stimulates cannabinoid receptorslocated in specific regions of the brain. (See Figure4.21.) Two types of cannabinoid receptors, and CB2,both metabotropic, have since been discovered. receptors are found in the brain, especially in thefrontal cortex, anterior cingulate cortex, basal ganglia,cerebellum, hypothalamus, and hippocampus. Very lowlevels of receptors are found in the brain stem,which accounts for the low toxicity of THC. recep-tors are found outside the brain, especially in cells of theimmune system.

THC produces analgesia and sedation, stimulatesappetite, reduces nausea caused by drugs used to treatcancer, relieves asthma attacks, decreases pressure withinthe eyes in patients with glaucoma, and reduces thesymptoms of certain motor disorders. On the otherhand, THC interferes with concentration and memory,alters visual and auditory perception, and distorts per-ceptions of the passage of time (Iversen, 2003). Devaneet al. (1992) discovered the first natural ligand for theTHC receptor: a lipidlike substance that they namedanandamide, from the Sanskrit word ananda, or “bliss.”A few years after the discovery of anandamide,Mechoulam et al. (1995) discovered another endo-cannabinoid, 2-arachidonyl glycerol (2-AG).

Anandamide seems to be synthesized on demand;that is, it is produced and released as it is needed and isnot stored in synaptic vesicles. It is deactivated by anenzyme, FAAH (fatty acid amide hydrolase), which is

CB2

CB1

CB1

CB1

present in anandamide-secreting neurons. Because theenzyme is found there, molecules of anandamide mustbe transported back into these neurons, which is accom-plished by anandamide transporters. Besides THC, sev-eral drugs have been discovered that affect the actionsof the endocannabinoids. receptors are blocked bythe drug rimonabant, the enzyme FAAH is inhibited byMAFP, and reuptake is inhibited by AM1172.

receptors are found on terminal buttons ofglutamatergic, GABAergic, acetylcholinergic, nora-drenergic, dopaminergic, and serotonergic neurons,where they serve as presynaptic heteroreceptors, regu-lating neurotransmitter release (Iversen, 2003). Whenactivated, the receptors open potassium channels in theterminal buttons, shortening the duration of actionpotentials there and decreasing the amount of neuro-transmitter that is released. When neurons releasecannabinoids, the chemicals diffuse a distance ofapproximately 20 μm in all directions, and their effectspersist for several tens of seconds. The short-term mem-ory impairment that accompanies marijuana useappears to be caused by the action of THC on receptors in the hippocampus. Endocannabinoids alsoappear to play an essential role in the reinforcingeffects of opiates: A targeted mutation that prevents theproduction of receptors abolishes the reinforcingeffects of morphine but not of cocaine, amphetamine,or nicotine (Cossu et al., 2001). These effects ofcannabinoids are discussed further in Chapter 18.

I mentioned three paragraphs ago that THC (and,of course, the endocannabinoids) have an analgesiceffect. Agarwal et al. (2007) found that THC exerts itsanalgesic effects by stimulating receptors in theperipheral nervous system. In addition, a commonlyused over-the-counter analgesic, acetaminophen (knownas paracetamol in many countries), also acts on thesereceptors. Once it enters the blood, acetaminophen isconverted into another compound that then joins witharachidonic acid, the precursor of anandamide. Thiscompound binds with peripheral receptors andactivates them, reducing pain sensation. Administrationof a antagonist completely blocks the analgesiceffect of acetaminophen (Bertolini et al., 2006).

CB1

CB1

CB1

CB1

CB1

CB1

CB1

FIGURE 4.21 ■ Cannaboid Receptors in a .Rat Brain.

In this autoradiogram the brain has been incubated in asolution containing a radioactive ligand for cannabinoidreceptors. The receptors are indicated by dark areas.(Autoradiography is described in Chapter 5.) (Br St brainstem, Cer cerebellum, CP caudate nucleus/putamen,Cx cortex, EP entopeduncular nucleus, GP globuspallidus, Hipp hippocampus, SNr substantia nigra.)

(Courtesy of Miles Herkenham, National Institute of Mental Health,Bethesda, MD.)

=====

===

Cx

CP

THC The active ingredient in marijuana; activates receptorsin the brain.

anandamide (a nan da mide) The first cannabinoid to bediscovered and probably the most important one.

FAAH Fatty acid amide hydrolase, the enzyme that destroysanandamide after it is brought back into the cell by anandamidetransporters.

rimonabant A drug that blocks receptors.

MAFP A drug that inhibits FAAH; prevents the breakdown ofanandamide.

AM1172 A drug that inhibits the reuptake of anandamide.

CB1

CB1

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NucleosidesA nucleoside is a compound that consists of a sugar mol-ecule bound with a purine or pyrimidine base. One ofthese compounds, adenosine (a combination of riboseand adenine), serves as a neuromodulator in the brain.

Adenosine is known to be released, apparently byglial cells as well as neurons, when cells are short of fuelor oxygen. The release of adenosine activates receptorson nearby blood vessels and causes them to dilate,increasing the flow of blood and helping to bring moreof the needed substances to the region. Adenosine alsoacts as a neuromodulator, through its action on at leastthree different types of adenosine receptors. Adenosinereceptors are coupled to G proteins, and their effect isto open potassium channels, producing inhibitory post-synaptic potentials. Because adenosine is present in allcells, investigators have not yet succeeded in distinguish-ing neurons that release this chemical as a neuromodu-lator. Thus, circuits of adenosinergic neurons have notyet been identified.

Because adenosine receptors suppress neural activity,adenosine and other adenosine receptor agonists havegenerally inhibitory effects on behavior. In fact, as we willsee in Chapter 9, there is good evidence that adenosinereceptors play an important role in the control of sleep.For example, the amount of adenosine in the brainincreases during wakefulness and decreases duringsleep. In fact, the accumulation of adenosine after pro-longed wakefulness may be the most important cause ofthe sleepiness that ensues. A very common drug,caffeine, blocks adenosine receptors (step 7 of Figure4.5) and hence produces excitatory effects. Caffeine is abitter-tasting alkaloid found in coffee, tea, cocoa beans,and other plants. In much of the world a majority of theadult population ingests caffeine every day—fortunately,without apparent harm. (See Table 4.3.)

Prolonged use of caffeine leads to a moderateamount of tolerance, and people who suddenly stop tak-ing caffeine complain of withdrawal symptoms, whichinclude headaches, drowsiness, and difficulty in concen-trating. If the person continues to abstain, the symptomsdisappear within a few days. Caffeine does not producethe compulsive drug-taking behavior that is often seenin people who abuse amphetamine, cocaine, or the opi-ates. In addition, laboratory animals do not readily self-administer caffeine, as they do drugs that are commonlyabused by humans.

Soluble GasesRecently, investigators have discovered that neurons useat least two simple, soluble gases—nitric oxide and car-bon monoxide—to communicate with one another.One of these, nitric oxide (NO), has received the most

attention. Nitric oxide (not to be confused with nitrousoxide, or laughing gas) is a soluble gas that is producedby the activity of an enzyme found in certain neurons.Researchers have found that NO is used as a messengerin many parts of the body; for example, it is involved inthe control of the muscles in the wall of the intestines, itdilates blood vessels in regions of the brain that becomemetabolically active, and it stimulates the changes inblood vessels that produce penile erections (Culottaand Koshland, 1992). As we will see in Chapter 14, NOmay also play a role in the establishment of neuralchanges that are produced by learning.

All of the neurotransmitters and neuromodulatorsdiscussed so far (with the exception of anandamide andperhaps adenosine) are stored in synaptic vesicles andreleased by terminal buttons. Nitric oxide is producedin several regions of a nerve cell—including dendrites—and is released as soon as it is produced. More accu-rately, it diffuses out of the cell as soon as it is produced.

adenosine (a den oh seen) A nucleoside; a combination of riboseand adenine; serves as a neuromodulator in the brain.

caffeine A drug that blocks adenosine receptors.

nitric oxide (NO) A gas produced by cells in the nervous system;used as a means of communication between cells.

Based on data from Somani and Gupta, 1988.

ITEM CAFFEINE CONTENT

Chocolates

Baking chocolate 35 mg/oz

Milk chocolate 6 mg/oz

Beverages

Coffee 85 mg/5-oz cup

Decaffeinated coffee 3 mg/5-oz cup

Tea (brewed 3 minutes) 28 mg/5-oz cup

Cocoa or hot chocolate 30 mg/5-oz cup

Cola drink 30–46 mg/12-oz container

TABLE 4.3 ■ Typical Caffeine Content of .Chocolate and Several Beverages .

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It does not activate membrane-bound receptors but entersneighboring cells, where it activates an enzyme responsi-ble for the production of a second messenger, cyclic GMP.Within a few seconds of being produced, nitric oxide isconverted into biologically inactive compounds.

Nitric oxide is produced from arginine, an aminoacid, by the activation of an enzyme known as nitricoxide synthase. This enzyme can be inactivated (step 2 ofFigure 4.5) by a drug called L-NAME (nitro-L-argininemethyl ester).

You have undoubtedly heard of a drug calledsildenafil (more commonly known as Viagra), which is usedto treat men who have erectile dysfunction—difficultymaintaining a penile erection. As we just saw, nitric

oxide produces its physiological effects by stimulatingthe production of cyclic GMP. Although nitric oxidelasts only for a few seconds, cyclic GMP lasts somewhatlonger but is ultimately destroyed by an enzyme.Molecules of sildenafil bind with this enzyme and thuscause cyclic GMP to be destroyed at a much slower rate.As a consequence, an erection is maintained for alonger time. (By the way, sildenafil has effects on otherparts of the body and is used to treat altitude sicknessand other vascular disorders.)

InterimSummaryNeurotransmitters and NeuromodulatorsThe nervous system contains a variety of neurotransmitters,each of which interacts with a specialized receptor. The neu-rotransmitters that have received the most study are acetyl-choline and the monoamines: dopamine, norepinephrine,and 5-hydroxytryptamine (serotonin). The synthesis of theseneurotransmitters is controlled by a series of enzymes.Several amino acids also serve as neurotransmitters, themost important of which are glutamate (glutamic acid),GABA, and glycine. Glutamate serves as an excitatory neuro-transmitter; the others serve as inhibitory neurotransmitters.

Peptide neurotransmitters consist of chains of aminoacids. Like proteins, peptides are synthesized at the

ribosomes according to sequences coded for by the chromo-somes. The best-known class of peptides in the nervous sys-tem includes the endogenous opioids, whose effects aremimicked by drugs such as opium and heroin. One lipidappears to serve as a chemical messenger: anandamide, theendogenous ligand for the CB1 cannabinoid receptor.Adenosine, a nucleoside that has inhibitory effects on synap-tic transmission, is released by neurons and glial cells in thebrain. In addition, two soluble gases—nitric oxide and car-bon monoxide—can diffuse out of the cell in which they areproduced and trigger the production of a second messengerin adjacent cells.

This chapter has mentioned many drugs and theireffects. They are summarized for your convenience inTable 4.4.

nitric oxide synthase The enzyme responsible for the productionof nitric oxide.

TABLE 4.4 ■ Drugs Mentioned in This Chapter .

EFFECT ON SYNAPTICNEUROTRANSMITTER NAME OF DRUG EFFECT OF DRUG TRANSMISSION

Acetylcholine (ACh) Botulinum toxin Blocks release of ACh AntagonistBlack widow spider venom Stimulates release of ACh AgonistNicotine Stimulates nicotinic receptors AgonistCurare Blocks nicotinic receptors AntagonistMuscarine Stimulates muscarinic receptors AgonistAtropine Blocks muscarinic receptors AntagonistNeostigmine Inhibits acetylcholinesterase AgonistHemicholinium Inhibits reuptake of choline Antagonist

(continued)

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TABLE 4.4 ■ Drugs Mentioned in This Chapter (continued)

EFFECT ON SYNAPTICNEUROTRANSMITTER NAME OF DRUG EFFECT OF DRUG TRANSMISSION

Dopamine (DA) L-DOPA Facilitates synthesis of DA AgonistAMPT Inhibits synthesis of DA AntagonistReserpine Inhibits storage of DA in synaptic vesicles AntagonistChlorpromazine Blocks D2 receptors AntagonistClozapine Blocks D4 receptors AntagonistCocaine, methylphenidate Blocks DA reuptake AgonistAmphetamine Stimulates release of DA AgonistDeprenyl Blocks MAO-B Agonist

Norepinephrine (NE) Fusaric acid Inhibits synthesis of NE AntagonistReserpine Inhibits storage of NE in synaptic vesicles AntagonistIdazoxan Blocks autoreceptors AgonistDesipramine Inhibits reuptake of NE AgonistMoclobemide Inhibits MAO-A AgonistMDMA, amphetamine Stimulates release of NE Agonist

Serotonin (5-HT) PCPA Inhibits synthesis of 5-HT AntagonistReserpine Inhibits storage of 5-HT in synaptic vesicles AntagonistFenfluramine Stimulates release of 5-HT AgonistFluoxetine Inhibits reuptake of 5-HT AgonistLSD Stimulates 5-HT2A receptors AgonistMDMA Stimulates release of 5-HT Agonist

Glutamate AMPA Stimulates AMPA receptor AgonistKainic acid Stimulates kainate receptor AgonistNMDA Stimulates NMDA receptor AgonistAP5 Blocks NMDA receptor Antagonist

GABA Allylglycine Inhibits synthesis of GABA AntagonistMuscimol Stimulates GABA receptors AgonistBicuculline Blocks GABA receptors AntagonistBenzodiazepines Serve as indirect GABA agonist Agonist

Glycine Strychnine Blocks glycine receptors Antagonist

Opioids Opiates (morphine, heroin, Stimulates opiate receptors Agonistetc.)

Naloxone Blocks opiate receptors Antagonist

Anandamide Rimonabant Blocks cannabinoid CB1 receptors AntagonistTHC Stimulates cannabinoid CB1 receptors AgonistMAFP Inhibits FAAH AgonistAM1172 Blocks reuptake of anandamide Agonist

Adenosine Caffeine Blocks adenosine receptors Antagonist

Nitric oxide (NO) L-NAME Inhibits synthesis of NO AntagonistSildenafil Inhibits destruction of cyclic GMPA Agonist

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Additional Resources 133

SUGGESTED READINGSCooper, J. R., Bloom, F. E., and Roth, R. H. The Biochemical Basis ofNeuropharmacology, 8th ed. New York: Oxford University Press, 2003.

Grilly, D. M. Drugs and Human Behavior, 5th ed. Boston: Allyn andBacon, 2006.

Visit www.mypsychkit.com for additional review andpractice of the material covered in this chapter. WithinMyPsychKit, you can take practice tests and receive acustomized study plan to help you review. Dozens ofanimations, tutorials, and Web links are also available.

You can even review using the interactive electronic ver-sion of this textbook. You will need to register forMyPsychKit. See www.mypsychkit.com for completedetails.

ADDITIONAL RESOURCES

Meyer, J. S., and Quenzer, L. F. Psychopharmacology: Drugs, the Brain,and Behavior. Sunderland, MA: Sinauer Associates, 2005.

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Physiology of Behavior 10e Ch04[1]