ICHAS, Inc. Addiction Science Westville

8/8/2019 ICHAS, Inc. Addiction Science Westville

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ICHAS, Inc. 2010 1

Addiction Sciencethe neuroscientific basis of drug use and abuse


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1. WHAT IS ADDICTION ?

Addiction an obsessive, compulsive, or excessive

psychological dependence

drug addiction obsessive gambling compulsive overeating

a chronic neurobiologic disorder with psychological, social, genetic,

environmental, even genetic dimensions


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Whats Addiction Science?


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History of Drug Use and Abuse

Exploration: explore nature, the mind or

inner self.

Top: South American Indians using yopo aDMT containing snuff. (R. E. Schultes). Below

left: carved stone head from Colombia shows acoca user, cheek bulged out with leaves dates

back about 1400ce. (Michael Aldrich), Belowright: Oliver Wendell Holmes, the nineteenth-

century American physician, poet, and author,

experimented with psychoactive effect of ether.

Religious practices: used to transcend

reality or experience the supernatural

Alter moods: relieve anxiety, depression,

lethargy, insomnia or boredom.

Treat disease: opium, morphine, andalcohol were mainstays of 19th century

medicine.


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Medical Classification of Addiction

DSM-IV-TR (American PsychiatricAssociation, 2000)

Addiction implies psychological dependence

A mental problem, not just a physical ailment

You can be addicted without physical dependence


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Signs and Symptoms of Addiction

You dont know what symptoms

someone is experiencing unless

they tell you.

Extreme mood changes Sleeping pattern changes Very tired or energetic Weight loss or weight gain

Coughs or sniffles Seeming unwell Pupils smaller or larger Secretiveness Lying Stealing

Financial instability Changes in social groups Unexplained outings Drug paraphernalia Drug stash

These signs occur across many

(but not all) addictions:

You may see signs in some

abusers but not others.


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2. TYPES AND FORMS OF ADDICTION

Addictions may develop to substances, behaviors or activities.

Gambling, food, sex, video games, etc just as devastating!

Every addiction is fueled in a slightly different way.

Some addicts are angry, others are fueled by self pity.

Most experience some level of fear and anger.

Guilt, shame and remorse add to the mix.


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Physical Dependence

specific behaviors and symptoms consequence of tolerance development sudden discontinuation of drug administration of drug antagonist activation of homeostatic mechanisms

Homeostatic Mechanisms and PharmacologicalAdaptations

abuser may stop making endogenous ligands, but instead

produce opposing chemicals

e.g. chronic use of sedatives results in higher levels of the

stimulating neurotransmitter glutamate. High levels of glutamate

kill nerve cells, excitatory neurotoxicity


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Psychological Dependence

psychostimulants elevate stimulatory neurotransmitters dont cause strong physical dependence

Depression of the reward system dysphoria


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Tolerance and Sensitization

Pharmacodynamic tolerance is a phenomenon where the effective

dose needs to be continually increased. e.g. organonitrates, opiates.

Cross Tolerance, Differential Tolerance, Pharmacokinetic Tolerance

Drug tolerance and sensitization are not defining characteristics of

addiction, but typically accompany addiction to certain drugs.

e.g. sedatives, psychostimulants (MDMA).

Sensitization of pharmacologic response occurs when equivalent orgreater effects occur at lower dose.

e.g. alcohol, anticoagulants, vasodilators


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Alcoholic Sensitization

Occurs in connection with liver damage

or reduced metabolic efficiency.


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Neurotoxic Effects of MDMA in the Squirrel

Monkey

HN

CH3

CH3

O

O


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Verbal Intoxication

Verbal Intoxication(Morgan, 1998, Parrott et al, 2000)

psychomotor impairment

pervasively hyperactive

Matching Familiar Figures Test(MFFT; Kagan, ChildDevelopment, 36, 609-628, 1965)

identify target from five similar foils.


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Proteresis: MDMA Tolerance

MDMA plasma concentration

remains relatively constant

from 2 to 4 hours post dose.

Verbal Intoxication falls from

50 to 15 over the same period


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3. NERVOUS SYSTEM BASICS: CNS and PNS

control and communication center brain and spinal cord sensory and motor nerves

interneurons neurotransmitters action potentials


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Synaptic Communication between Neurons

Neurotransmission presynaptic neuron acquires action potential action potential opens Ca2+ ion channels Ca2+ initiates release of NT from terminal NT binds receptor on dendrite postsynaptic neuron acquires action potential


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Drug/Neurotransmitter Interactions


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Brain Structures and Behavior

Frontal lobe of the cerebral cortex is

associated with reasoning, planning,

parts of speech, movement, emotions,

and problem solving.

Limbic System emotional brain it

contains:

Thalamus Hypothalamus Amygdala Hippocampus

Frontal Lobotomy

severe emotional disorders removes limbic/FC connections loss of concentration, planning

Cingulate Gyrus Coordinates Sensory/Emotion inputs Emotional Responses to Pain Regulates Aggressive Behavior


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4. DOPAMINERGIC REWARD SYSTEM

Dopamine concentration increases in the

limbic (mid-brain) regions.

Pleasure senses:

elation

well-being clarity, and release

Serotonin

happiness, aggression altered perceptions, psychosis

Volume losses in the frontal lobe is foundin drug abuser.

Reduced PFC function impairs top-down

processes and willed behaviors.Loss of inhibitory controls.

Default to stimulus-driven behaviors,

facilitated by abuse.


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Dopamine Release by Addictive Substances

Opiates: mu-opioid receptors located inGABAergic neurons block inhibitory effects on DA

firing by VTA. Kappa-opioids decrease DA.

Cannabinoids: mu-opioid antagonist preventTHC induced release of DA by VTA. Mechanism may

involve dopaminergic neuron dis-inhibition.

Psychostimulants: Block DA, 5-HT and NEreuptake transporters in NAc. Indirect inhibition of

GABAergic signaling to the VTA.

Ethanol: Enhances release of DA from VTA.Inhibits NMDA glutamate receptors, facilitates

GABAa receptors

Sedatives: Work at various GABA receptorallosteric sites. May not increase DA reward.

Nicotine: Bind directly to Ach receptors ondopaminergic neurons in the VTA. Increase DA firing


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Long-Term Potentiation and Depression

Long-term depression (LTD): decreased responsiveness of a

postsynaptic neuron induced by repeated weak stimulated.

Long-term potentiation (LTP): enhanced responsiveness of apostsynaptic neuron induced by repeated action potentials that

strongly depolarized the neuron.

LTP is associated with presynaptic release ofglutamate.


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Glutamate Sensitization in LTP

Glutamate released byactivated presynapticterminal opens non-NMDAglutamate receptor

channels.

Na+ influx follows thatdepolarizes postsynapticmembrane

Depolarization removesthe Mg2+ block from

NMDA-receptor channel,which (glutamate bound)now allows Ca2+ to enterthe postsynaptic cell

Increased Ca2+ in thecytosol inducespostsynaptic cell to insertnew non-NMDA glutamatereceptors in the

membrane, increasing cellsensitivity to glutamate


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LTP at Dopaminergic Neurons


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Sugar Addiction

Above: After14 days of abstinence, rats that previously had 12-h dailyaccess significantly increased lever pressing for glucose to 123% of pre-

abstinenceresponding. Avena et al., 2004

Left: Extracellular DA (upper graph) decreased to 81% of baseline.Acetylcholine (lower graph) increased to 157% in the same intermittent

sugar-access rats. No effects were seen in a control group with Adlibitum Chow followed by a naloxone injection. Colantuoniet al., 2002


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Addiction Liability Studies

Rate of absorption is associated abuse potential for substance abuse.

e.g. crack rapid onset of action.

e.g. increased rate ofdiazepam ornicotine.

Addiction liability can be studied in

animal models since the mechanisms

of addiction are universal.

Any substance evokes addiction in a rat or mouse will produce addiction in humans as well


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Comparison of Nicotine Absorption Rates


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Animal Self-Administration Studies:

Heroin vs. Cocaine

Bottom left. Addictive liability of four

drugs. Graph plots %responses (drug

vs. food) against dose.

Drug with zero abuse liability food was

preferred to drug >50%.

Top right. Monkeys given lever self-

administration (drug vs. food). Plots drug

lever percent for heroin/cocaine.

Monotonic dose-dependency.

Bottom right. Response rate is dose

dependent but bimodal.

Top left. Compares heroin/cocaine

addictive liability. The graph plots

#reinforcers (drug injections) against

drug dose.

Addictive liability is dose dependent.


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5. CYCLE OF ADDICTION


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Drug Type vs Withdrawal

Drug Overdose Effects Withdrawal Symptoms

Amphetamines, Cocaine,

Methylphenidate

Agitation, hypertension,

tachycardia, delusions,

hallucinations,

hyperthermia, seizures,death

Apathy, irritability,

increased sleep time,

disorientation, depression.

Barbiturates,

Benzodiazepines, Ethanol

Slurred speech, drunken

behavior, dilated pupils,

weak/rapid pulse, clammy

skin, shallow respiration,

coma, death

Anxiety, insomnia,

delirium, tremors, seizure,

death

Opioids Constricted pupils,

clammy skin, nausea,

drowsiness, respiratory

depression, coma, death

Nausea, chills, sweets,

cramps, lacrimation,

rhinorrhea, yawning,

hyperpnea, tremor


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Corticotrophin-Releasing Factor(CRF) and

Neuropeptide Y (NPY)

CRF: causes anxiety-like behavior during withdrawal. causes DYN release, inhibits DA firing of VTA

NPY: widely distributed in the CNS. binding sites in regions implicated in withdrawal

inhibitory effects on withdrawal

reduced levels result from chronic abuse

+ =


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Extracellular CRF Levels of the Amgydala During Cocaine

Self-Administration and Subsequent Withdrawal

CRF produces arousal, stress-like

responses, and a dysphoric,

aversive state.

Dependence syndrome can be

reversed by blockade of CRF

function.


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Extracellular CRF Levels in the Central

Amygdala During Ethanol Withdrawal

Chronic alcohol exposure produces a

dependence syndrome that is

reversed by blockade of CRF function.

CRF antagonist: when injected into

amygdala blocks anxiogenic effects of

alcohol withdrawal.


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6. ADDICTION EPIDEMIOLOGY

Many environmental factors contribute to a

persons propensity to abuse. These include:history of physical or sexual abuse, witnessing violence, orother social stressors. Drug availability is a primaryenvironmental factor.

Substance abusers experience higher rates of

other mental illnesses than general population.Converse is also true.

A developmental disease that usually begins in

adolescence. For example, 67 percent of those who trymarijuana for the first time are 12 to 17yrs.


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Hereditary Predispositions of Addiction

Evidence for genetic influences on

alcoholism, opiate dependence and

other CNS depressants is emerging.

Genes only increase vulnerability.

Vulnerability to depression/ anxiety

may contribute to drug dependence.


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Genetic and Environmental Factors in Alcohol

Abuse


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Scientific Research:

Addicted Twins, Genes Targets


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Global Addiction Patterns

OpioidsCannabinoids

CocaineAmphetamine

OtherNo data


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Addiction in U.S. Communities

Race/Ethnicity

Current illicit drug use among persons

aged 12 or older.

2008 Rates

14.7% Multiracial

10.1% Blacks

9.5%American Indians (Alaska Natives)

8.2% Whites

7.3% Hawaiians (Pacific Islanders)

6.2% Hispanics

3.6%Asians


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7. TREATMENT AND ADDICTION

MANAGEMENT


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Detoxification

Detoxification is the medically managed withdrawal of individuals from a substance onwhich they are physiologically dependent.

Cross-tolerance is the ability of one drug or substance to act as a physiologic substitutefor another. Using a cross-tolerant substitute allows the dependent individual to detoxwithout experiencing a withdrawal syndrome.

Comprehensive Serum Chemistry Panel includes, at minimum: glucose,electrolytes, BUN, creatinine, albumin, bilirubin,AST, and ALT.

Kindling, a phenomenon in which the severity of withdrawal symptoms increases afterrepeated withdrawal episodes, is experienced by many alcoholics. Patients should betreated aggressively to reduce the severity ofwithdrawal symptoms.

Kindling may contribute to a patients relapse risk and to alcohol-related brain damage andcognitive impairment.


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Medications Used to Treat Drug Addiction

Tobacco Addiction

Nicotine replacement therapies (e.g., patch, inhaler, gum) Bupropion

Varenicline

Opioid Addiction

Methadone

Buprenorphine

Alcohol and Drug Addiction

Naltrexonehelpspreventrelapseto alcohol and heroin abuse Disulfiramhelpspreventrelapseto alcohol and cocaine abuse Acamprosatehelpspreventrelapseto alcohol abuse


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Drug Abuse-Related Diseases

Medical Consequences of AddictionIllicit drug abuse causes 17,000 deaths annually in the U.S. and more than $180 billion in annual economiccosts. Abuse of nicotine, alcohol, and/or prescription drugs causes additional morbidity and mortality.(http://www.nida.nih.gov/consequences/).

Cardiovascular effects.

Researchers have found a connection between abuse and cardiovascular disease. IV drug use can alsolead damaged blood vessels and bacterial infections e.g. marijuana, psychostimulants, and inhalants.

Neurological effects.Some drugs cause seizures, stroke, and widespread brain damage. Chronic drug use can lead to problemswith memory, attention, and decision-making. e.g. cocaine, methamphetamine, inhalants, and ecstasy.

HIV, hepatitis, and other infectious diseases.IV use of heroin, cocaine, and methamphetamine causes more than a third of new AIDS cases and is amajorcontributor to the spread of hepatitis C.

Other health effects.Withdrawal from drug use also may lead to adverse health effects, including restlessness, mood swings,fatigue, muscle and bone pain, insomnia, cold flashes, diarrhea, and vomiting.


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Drug Rehabilitation

Cognitive Behavioral Therapy

Seeks to help patients recognize, avoid, and cope with cues fordrug abuse.

Motivational Incentives

Uses positive reinforcement i.e. rewards or privileges for remaining drug free.

Motivational Interviewing

Strategies to evoke internally motivated change in addictive behaviors.

Group Therapy

Learn effective ways to solve interpersonal problems without addiction.


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ACKNOWLEDGEMENTS ?


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Documents

ICHAS, Inc. Addiction Science Westville