I. Introduction

II. Neural and Neurochemical Bases of Reward and ActionA. Discovery of rewarding electrical brain stimulation (self-stimulation)

B. Rewarding brain stimulation and conventional motivation and reward

C. A punishment system

D. Theories of self-stimulation

E. Neural and neurochemical substrates of self-stimulation

F. Dopamine systems

G. The relationship between self-stimulation and drug self-administration (i.e., drugs which act as reinforcers)

H. Conditioned place preference: use for assessing reinforcing properties of drugs

I. Neural substrates of drug addiction

J. Neurochemistry and neuropharmacology of reward systems

K. Relation of motivation and reward systems to motor pathways: from motivation to action

III. Overview of Drug Abuse, Addition and Dependence A. Definitions

B. Toxicity of drugs of abuse

C. Origins of abuse and dependence

D. DSM-IV and ICD-10 criteria

E. Variables associated with abuse and addiction

F. Theories of addiction

IV. Treatments for Drug DependenceA. Detoxification

B. Maintenance of abstinence

C. Strategies and therapeutics241-4.0

31:241 Behavioral and Cognitive Neuroscience31:241 Behavioral and Cognitive NeuroscienceProfessor A.K. JohnsonProfessor A.K. Johnson

Fall 2012Fall 2012 Outline Outline

Reward and AddictionReward and Addiction10/30; 11/110/30; 11/1

Key Terms and ConceptsKey Terms and Concepts

Abstinence syndromeDependenceDepressant (neural depressant)Dorsal mesostriatal (nigrostriatal) Drug abuseDrug sensitizationDrug toleranceMesocortical

MesolimbicNaloxoneNigrostriatalSensitizationStimulantsToleranceVentral mesostriatal (mesolimbic)Ventral pallidum

241-4 KTC

Operant Chamber (Skinner Box)Operant Chamber (Skinner Box)for Delivery of Rewarding Electricalfor Delivery of Rewarding ElectricalBrain Stimulation (Self-Stimulation)Brain Stimulation (Self-Stimulation)

241-4.1

A Cumulative Bar-Pressing Curve for a Self-Stimulating A Cumulative Bar-Pressing Curve for a Self-Stimulating Rat With an Electrode in a Positive Reward SiteRat With an Electrode in a Positive Reward Site

241-4.2

The Relationship Between Self-Stimulation and The Relationship Between Self-Stimulation and Conventional Motivated Behaviors and RewardConventional Motivated Behaviors and Reward

241-4.3

• Performance on instrumental tasks- Reward magnitude- Priming- Rapid extinction- Schedules of reinforcement- Chaining of behaviors- Secondary reinforcers

• Electrically elicited behaviors (drinking, eating, chewing, hoarding, aggressive reproductive responses)

• Aversion/punishment systems

Some Sites Which Support Intracranial Self-Some Sites Which Support Intracranial Self-Stimulation in Various Animal SpeciesStimulation in Various Animal Species

241-4.4

Brain Area Sites Which Support Self-StimulationForebrain Frontal cortex; Entorhinal cortex;

Olfactory nucleus; Caudate nucleus;Nucleus accumbens; Entopeduncular nucleus;Septal area; Hippocampus;Amygdaloid nucleus; Ventral and medial

thalamus;Hypothalamus Median forebrain bundle;

Dorsal noradrenergic bundle

Midbrain and Ventral tegmental area; Substantia nigra;brain stem Raphe nuclei; Nucleus coeruleus;

Superior cerebellar Periaqueductal gray matter peduncle;Mesencephalic nucleus of trigeminal nerve

Cerebellum Deep cerebellar nuclei Other cerebellar areas

MedullaMotor nucleus of trigeminal nerve;Nucleus of tractus solitarius

Neuroanatomy of Brain RewardNeuroanatomy of Brain Rewardand Punishment Systemsand Punishment Systems

241-4.5

Theories of Self-StimulationTheories of Self-Stimulation

241-4.6

• Automatistic behavior

• Hedonic (Olds)

• Dual activation of drive and reward pathways (Deutsch; Gallistel)

• Consummatory behavior (Glickman & Schiff)

• Incentive motivation (Trowill, Panksepp & Gandelman)

Lines of Evidence Supporting the Idea that Catecholamines Lines of Evidence Supporting the Idea that Catecholamines (CAs) Mediate Rewarding Brain Stimulation(CAs) Mediate Rewarding Brain Stimulation

Larry Stein(Circa 1966)

241-4.7

• Drugs that facilitate self-stimulation release CAs (e.g., amphetamine).

• Drugs that inhibit self-stimulation deplete CAs (reserpine, -methyl-p- tyrosine).

• Drugs that block adrenergic transmission (chlorpromazine) inhibit self-stimulation.

• Protection of CAs with monoamine oxidase inhibitors or block reuptake (e.g., imipramine) enhances the facilitatory effect of amphetamine on self-stimulation.

• Depletion of brain CAs with reserpine or -methyl-p-tyrosine decreases the facilitatory effects of amphetamine on self-stimulation.

• A large component of the medial forebrain bundle (MFB), a “hot-spot” for self-stimulation, is catecholaminergic.

• Rewarding stimulation of the MFB causes release of norepinephrine into the amygdala and hypothalamus.

Horizontal and Lateral Representations of Ascending Horizontal and Lateral Representations of Ascending Noradrenaline and Dopamine PathwaysNoradrenaline and Dopamine Pathways

241-4.8

Dopaminergic Pathways in the Rat BrainDopaminergic Pathways in the Rat Brain

241-4.9

The Four Major DA Pathways in the BrainThe Four Major DA Pathways in the Brain

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Brain Dopamine SystemsBrain Dopamine Systems

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Ultrashort

• Retina – interplexiform amacrine-like neurons

• Olfactory bulb – periglomerular dopamine cells

Intermediate Length

• Tuberohypophyseal

• Incertohypothalamus

• Medullary periventricular

Long Length

• Nigrostriatal

• Mesolimbic

• Mesocortical

The Dopamine SynapseThe Dopamine Synapse

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Six Types of Postsynaptic Dopamine ReceptorsSix Types of Postsynaptic Dopamine Receptors

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D1 and D5 D2a D2b D3 and D4

Molecular structure Seven membrane- Seven membrane- Seven membrane- Seven membrane-

spanning regions spanning regions spanning regions spanning regions

Effect on cyclic AMP Increases Decreases Increases phospho- ? inositide turnover

Agonists Dopamine Full agonist (weak) Full agonist (potent) Apomorphine Partial agonist (weak) Full agonist (potent)

Antagonists Phenothiazines Potent Potent Thioxanthenes Potent Potent Butyrophenones Weak Potent Clozapine Inactive Weak Weak Potent

The RotometerThe Rotometer

241-4.14

Investigation of the Actions ofInvestigation of the Actions ofDopamine in the Nigrostriatal System:Dopamine in the Nigrostriatal System:

Drug-Induced Rotational Behavior in Rats with Unilateral Nigrostriatal Lesions

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Some Prototypic Dopamine Agonists and AntagonistsSome Prototypic Dopamine Agonists and Antagonists

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Presumed Mechanism Most Prominent Drug of Action Physiological EffectsAntagonists Butyrophenones Haloperidol Phenothiazines Receptor blockade Tranquilizer; antipsychotic; antinauseant Chlorpromazine*Agonists Apomorphine Receptor stimulation Antiparkinsonian, emetic BromocriptineReleasers Amphetamine Releaser Stimulant, appetite suppressantVesicular Storage Inhibitors Reserpine* Depletion Antihypertensive; tranquilizer;

antipsychoticPump Inhibitors Cocaine Reuptake inhibition Stimulant euphoriantSynthesis Inhibitors Carbidopa Dopa decarboxylase inhibition Adjuvant for central dopa -Methyl-p-tyrosine* Tyrosine hydroxylase inhibition Depressant; akinesiaMonoamine Oxidase Inhibitors Iproniazid* Broad-spectrum MAO inhibition AntidepressantCOMT Inhibitors Tropolone, pyrogallol*, COMT inhibition Minimal effects rutin, quercetinFalse Transmitters -Methyldopamine* AntihypertensiveToxin 6-Hydroxydopamine* Destruction of cells ExperimentalPrecursors Dopa Stimulates transmitter production Antiparkinsonism and mild stimulant

*Also has prominent norepinephrine or epinephrine action, or both

The Medial Forebrain Bundle is One of the The Medial Forebrain Bundle is One of the "Hottest" Brain Pathways for Self-Stimulation"Hottest" Brain Pathways for Self-Stimulation

241-4.17

Blockade of Medial Forebrain Bundle Self-Blockade of Medial Forebrain Bundle Self-Stimulation by Dopamine Receptor Antagonist Stimulation by Dopamine Receptor Antagonist

Infused Into the Nucleus AccumbensInfused Into the Nucleus Accumbens

241-4.18

Effects of Electrical Self-StimulationEffects of Electrical Self-Stimulationof the Ventral Tegmental Area on Extracellular of the Ventral Tegmental Area on Extracellular

Dopamine in the Nucleus AccumbensDopamine in the Nucleus Accumbens

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Apparatus for Producing andApparatus for Producing andMeasuring a Conditioned Place PreferenceMeasuring a Conditioned Place Preference

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Place Conditioning With Dopamine AgonistsPlace Conditioning With Dopamine AgonistsInfused Into the Nucleus AccumbensInfused Into the Nucleus Accumbens

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Intravenous Self-Administration of Drugs of AbuseIntravenous Self-Administration of Drugs of Abuse

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Some Drugs Which Act asSome Drugs Which Act asReinforcers* in Animal SpeciesReinforcers* in Animal Species

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Alcohol MarijuanaAmphetamines MethadoneApomorphine Methyl phenidateBarbiturates MorphineBenzodiazepines NicotineChlorphentermine Nitrous oxideChloroform PentazocineClortermine PhencyclidineCocaine PhenmetrazineCodeine PipradrolDiethylpropion ProcaineEther PropiramLacquer, thinners Propoxyphene

*Animals will voluntarily self-administer these drugs after suitable priming, depending on dose, schedule, route of administration, and species. Routes of administration include: intravenous, intramuscular, inhalation, intracerebral, intragastric tube, and oral. Animal species include: rat, monkey, ape, baboon, dog, and others.

Mediation of the Rewarding Effects of Drugs of Abuse Mediation of the Rewarding Effects of Drugs of Abuse by Dopamine (DA) Action in the Nucleus Accumbensby Dopamine (DA) Action in the Nucleus Accumbens

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Hypothesized Sites of Action of DrugsHypothesized Sites of Action of Drugson Brain-Reward Circuitry in the Raton Brain-Reward Circuitry in the Rat

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Changes in Dopamine Detected in the Extracellular Changes in Dopamine Detected in the Extracellular Fluid of the Nucleus Accumbens of Rats After Daily Fluid of the Nucleus Accumbens of Rats After Daily

Intraperitoneal Cocaine Injections (10 mg/kg)Intraperitoneal Cocaine Injections (10 mg/kg)

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Tetrahydrocannabinol (THC)-Induced EnhancementTetrahydrocannabinol (THC)-Induced Enhancementof Dopamine Efflux in the Nucleus Accumbensof Dopamine Efflux in the Nucleus Accumbens

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Two Systems Responsible for theTwo Systems Responsible for theInitiation of Movements (Actions):Initiation of Movements (Actions):

One Involves Cognitive Processes and the Other Involves Those in Response to Basic Motivations (Drives) and Emotions

241-4.28

Cer

ebra

l C

ort

ex

Lim

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Str

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ure

s

Glo

bu

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alli

du

sCaudate N.(Neostriatum)

N. Accumbens(Ventral Striatum)

VTA

DAA10

MotorSystem

Locomotion Occurs When InhibitoryLocomotion Occurs When Inhibitory GABA-Secreting Synapses on Neurons GABA-Secreting Synapses on Neurons

in the Globus Pallidus Decrease Their Activityin the Globus Pallidus Decrease Their Activity

241-4.29

The Motive Circuit "Translates" theThe Motive Circuit "Translates" thePerception of a Reward Into LocomotionPerception of a Reward Into Locomotion

241-4.30

Simplified Diagram of CentralSimplified Diagram of CentralPathways Controlling LocomotionPathways Controlling Locomotion

241-4.31

Ce

reb

ral

Co

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x

Lim

bic

Str

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ture

s Glo

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Thalamus

N. Accumbens(Ventral Striatum)

VTA

MotorSystem

Caudate N.(Neostriatum)

Me

se

nc

ep

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Lo

co

mo

tor

Re

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un

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Spinal Pattern

Generator

NRP

VentromedialMedulla

NRP

VTA, ventral tegmental area; NRG, nucleus reticularis gigantocellularis; NRP, nucleus reticularis pontis oralis

Drug Dependence and AbuseDrug Dependence and Abuse

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Drug Abuse = a maladaptive pattern of substance use manifested by recurrent and significant adverse consequences to repeated use of substances.

Dependence• Drug dependence is a state whereby an individual either

psychologically or physically requires a drug in order to

feel well in the absence of medical indications.

• Discontinuation of the drug will produce a characteristicgroup of withdrawal symptoms.

• Physiological dependence = adverse physiologicalreactions (e.g., stomach cramps) in the absence of

drugs.

• Primary psychological dependence = produces pleasureand/or reduces "psychic" discomfort (drug craving).

• Secondary psychological dependence = fear or anxiety as

a result of a lack of drug.

Drug Addiction = Substance DependenceDrug Addiction = Substance Dependence

1. Compulsion to seek and take a drug.

2. Loss of control in limiting intake.

3. Emergence of negative emotional state (e.g., dysphoria, anxiety, irritability) when access to drug is prevented.

4. Chronic relapsing disorder.

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Categories of Drugs of AbuseCategories of Drugs of Abuse

241-4.34

Opiates and Opioids• Morphine, codeine, heroin, meperidine, hydromorphone,

and other opioid agonists

Stimulants• Cocaine, amphetamines, methylphenidate, nicotine,

caffeine

Depressants• Barbiturates, non-barbiturate sedatives, benzodiazepines,

and ethanol

Hallucinogens• D-lysergic acid diethylamide (LSD), mescaline,

methylenedioxymethamphetamine (MDMA), phencyclidine, marijuana

Inhalants

Classification of Drug UseClassification of Drug Use

1. Occasional, controlled, social use

2. Abuse or harmful use

3. Addiction

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Drug Use, Abuse and DependenceDrug Use, Abuse and Dependencein U.S. Adultsin U.S. Adults

At Some Point in Their Lifespan

• 15.6% engage in illicit drug use

• 3.1% engage in abuse

• 2.9% develop dependence

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DSM-IV and ICS-10 Diagnostic Criteria for DSM-IV and ICS-10 Diagnostic Criteria for Alcohol and Drug Abuse/Harmful UseAlcohol and Drug Abuse/Harmful Use

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DSM-IV Alcohol and Drug Abuse

A. A maladaptive pattern of substance use leading to clinically significant impairment or distress, as manifested by one (or more) of the following, occurring within a 12 month period:

1. Recurrent substance use resulting in a failure to fulfill major role obligations atwork, school, or home.

2. Recurrent substance use in situations in which it is physically hazardous.

3. Recurrent substance-related legal problems.

4. Continued substance use despite having persistent or recurrent social orinterpersonal problems caused or exacerbated by the effects of the drug.

B. The symptoms have never met the criteria for substance dependence for this class of substances.

ICD-10 Harmful Use of Alcohol and Drugs

A. A pattern of substance use that is causing damage to health. The damage may be physical or mental. The diagnosis requires that actual damage should have been caused to the mental or physical health of the user.

B. No concurrent diagnosis of the substance dependence syndrome for same class of substance.

DSM-IV and ICD-10 Diagnostic Criteria for DSM-IV and ICD-10 Diagnostic Criteria for Alcohol and Drug DependenceAlcohol and Drug Dependence

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Stages of Drug Addiction/DependenceStages of Drug Addiction/Dependence

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Diagnostic Criteria of AddictionDiagnostic Criteria of Addiction

• Shift in emphasis in diagnostic criteria from focus on tolerance and withdrawal to criteria related to compulsive use.

• Diagnostic and Statistical Manual of Mental Disorders = DSM-IV (American Psychiatric Association)

• International Statistical Classification of Diseases and Related Health Problems = ICD-I0 (World Health Organization)

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Origins of Abuse and DependenceOrigins of Abuse and Dependence

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• Drugs that affect behavior are likely to be taken in excess when the effects are considered pleasurable.

• Legal prescription drugs (e.g., barbiturates, morphine, amphetamine), illegal drugs (e.g., heroin and cocaine) and non-prescription drugs (e.g., ethanol and nicotine) are abused and can produce dependence.

• Very few individuals begin addiction problems by misuse of prescription drugs.

• However, prescribed medications for pain, anxiety and even hypertension commonly produce tolerance and physical dependence.

• Tolerance and physical dependence do not imply abuse or addiction.

Vulnerability to AddictionVulnerability to Addiction

Individual Differences:

• Temperament--Disinhibition--Negative affect--Novelty/sensation seeking

• Social Development--Early drug/alcohol exposure

• Co-morbidity--Mood disorders--Anxiety disorders--Antisocial personality disorder--Conduct disorders

• Genetics--Contributes to ~40% of total variability associated with drug dependence

• Protective Factors--Also receives contributions from genetics, personality, and environment

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Abstinence SyndromeAbstinence Syndrome

241-4.43

• Physiological and psychological dependence-related symptoms and signs that arise during withdrawal of a drug.

- Relationship with ½ life of drug.

Relationship Between the Intensity of a Drug's Effects Relationship Between the Intensity of a Drug's Effects and the Intensity of the Abstinence Syndromeand the Intensity of the Abstinence Syndrome

241-4.44

Differences in ResponsesDifferences in Responsesto Heroin and Methadoneto Heroin and Methadone

241-4.45

Medical/Psychological Views of AddictionMedical/Psychological Views of Addiction1. Dependence ('40's)

--Physical dependence the sine qua non of the abstinence syndrome

--Evolved to include "psychic" (psychological) dependence

--Drug craving

2. Psychiatric

--Addiction has aspect of impulse control disorders and compulsive disorders

--Impulsive acts preceded by tension or arousal followed by pleasure gratification or relief

--Compulsive acts preceded by anxiety and stress followed by relief from stress

--Addiction considered to shift from an impulsive disorder to a compulsive disorder

--A circle of addiction with 3 stages: preoccupation/anticipation → binge/intoxication → withdrawal/negative affect

3. Psychodynamic

--Focuses on developmental difficulties, emotional disturbances, structural (ego) factors, personality organization and building of the self

--Associated with a self-medication hypothesis where users are considered to take drugs to cope with painful/threatening emotions

--Opiates for anger and rage

--Psychostimulants for anhedonia, anergia, and lack of feelings

--Neurodepressants for those flooded by or cut off from feelings

--Each drug class serves as an antidote for a dysphoric condition or state

4. Social Psychological/Self-Regulation

--Failure in self-regulation leads to addiction

--Initial lapse in self-regulation leads to large-scale breeder claims in self-regulation due to emotional distress

--Each successive lapse brings greater distress and a downward spiral ensues

--View can be related to neural processing concepts involving frontal lobe dysfunction

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Diagram Representing a Psychiatric View of the Diagram Representing a Psychiatric View of the Transition of a Problem of Impulse Control to a Problem Transition of a Problem of Impulse Control to a Problem of Compulsion in the Course of Becoming Addicted and of Compulsion in the Course of Becoming Addicted and

the Nature of Reinforcement (Positive to Negative)the Nature of Reinforcement (Positive to Negative)

241-4.47

Primary Goal of Neurobiological Primary Goal of Neurobiological Addiction Research:Addiction Research:

To Understand the Neuropharmacological and To Understand the Neuropharmacological and Neuroadaptive/Neuroplastic MechanismsNeuroadaptive/Neuroplastic Mechanisms Within the neurocircuitry mediating the transition between occasional drug use and the loss of control over drug seeking and taking (i.e., addiction).

241-4.48

Major Issues for a ComprehensiveMajor Issues for a ComprehensiveUnderstanding of Drug AddictionUnderstanding of Drug Addiction

241-4.49

• Reward mechanisms

• Changes in response to the drug (sensitization or tolerance)

• Drug craving

• Causes for relapse

Neuroadaptation Views of AddictionNeuroadaptation Views of Addiction1. Behavioral Sensitization

Berridge & Robinson Conceptually tied to psychomotor sensitization Incentive sensitization Liking and wanting Incentive-salience

--Cues associated with drug cues and drug taking become associated through Pavlovian stimulus associative conditioning to enhance motivation

2. Opponent-Process or Counteradaptation Theory Contributors used such theories to account for tolerance and withdrawal:

Himmelsbach ('40's) Martin ('60's) Solomon & Corbit ('70's) Koob & Bloom ('80's)

--Theorized that the brain uses negative feedback mechanisms to keep affective responses in check

--An unconditioned "a" process (positive/pleasurable) is counteracted by a "b" process--The "b" process has a larger latency of onset and duration of action--"b" process grows disproportionally compared to the decreasing "a" process and is associated

with an aversive craving state

--Solomon argues that the 'b" process "grows" with repeated drug taking3. Motivational

--Drug addicts frequently report that there is minimal pleasure derived from the drug although the craving is great

--The threshold for reward becomes elevated when drug is administered--Can be demonstrated by showing that ICSS thresholds are elevated by cocaine administration

4. Plasticity in Second Messenger and Immediate Early Gene Response Systems5. Allostasis

Allostasis = maintaining apparent reward function stability through changes in brain reward mechanisms Koob & Le Moal Propose: that not only does the opponent-process "b" change with repeated drug consumption but that the drug-reward "set point" also changes

241-4.50

Robinson and Berridge's TheoryRobinson and Berridge's Theoryof Incentive Salience and Drug Addictionof Incentive Salience and Drug Addiction

241-4.51

• Administration of some classes of abused drugs (e.g., psychostimulants) produce sensitization (i.e., reverse tolerance).

• For example, psychomotor stimulants increase locomotor behavior with spaced, repeated administration in a normal environment.

• Robinson and Berridge propose that increased drug craving is the produce of a similar sensitization process where "wanting" the drug is enhanced.

Berridge and Robinson's Model Focusing on the Berridge and Robinson's Model Focusing on the Role of Incentive Salience as a Factor Related to Role of Incentive Salience as a Factor Related to

Drug Craving and In Turn RelapseDrug Craving and In Turn Relapse

241-4.52

The Opponent-Process TheoryThe Opponent-Process Theoryof Motivation and Emotionof Motivation and Emotion

241-4.53

Koob and Le Moal's Application ofKoob and Le Moal's Application ofOpponent-Process Theory to Phenomenology Opponent-Process Theory to Phenomenology

Associated with Drug AddictionAssociated with Drug Addiction

241-4.54

Koob and Le Moal's Diagram of theKoob and Le Moal's Diagram of theHypothetical Spiraling Distress-AddictionHypothetical Spiraling Distress-Addiction

From a Neurobiological PerspectiveFrom a Neurobiological Perspective

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Nestler's Theory of Sensitization as aNestler's Theory of Sensitization as aResult of Drugs that Release DopamineResult of Drugs that Release Dopamine

Causing Increased Fos-Related Antigens (Fra)Causing Increased Fos-Related Antigens (Fra)

241-4.56

Behavioral and Cellular/Molecular Changes Behavioral and Cellular/Molecular Changes Associated with Drug Use, Addiction,Associated with Drug Use, Addiction,

Withdrawal and Long-Term Abstinence Withdrawal and Long-Term Abstinence

241-4.57

Treatment for Drug DependenceTreatment for Drug Dependence

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• Will vary with the drug being used and social and cultural factors determining the use.

• The management of withdrawal syndromes can be achieved with minimal risk and high probability of success using pharmacological agents.

Detoxification: Withdrawal of OpioidsDetoxification: Withdrawal of Opioids

241-4.59

• Most patients will perceive withdrawal symptoms.

• May be possible to reduce the drug.

• Methadone is suitable for suppressing withdrawal symptoms.

• With methadone substitution in an in-patient setting, symptoms usually aren't worse than "flu-like" syndrome.

• Under these "drug weaning" conditions, most patients can be withdrawn in less than 10 days.

• Clonidine (2-adrenergic receptor agonist) can suppress some components of opioid withdrawal.

• Clonidine suppresses autonomic signs and symptoms (e.g., nausea, vomiting, diarrhea) then drug craving.

Withdrawal of NeurodepressantsWithdrawal of Neurodepressants

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• Abrupt neurodepressant withdrawal can be fatal.

• Pentobarbital can be substituted for any neurodepressant.

• Pentobarbital is administered to induce mild intoxication and maintained 24 to 36 hrs and stabilized, then withdrawal can be started.

Role of PharmacologicalRole of PharmacologicalAgents Following WithdrawalAgents Following Withdrawal

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• Therapeutics may be used to treat underlying psychological problem (e.g., anxiety or depression).

• Therapeutic agents intended to be a less toxic substitute (e.g., methadone) may be used.

• Drugs to interfere with reinforcing actions of the abused drug (e.g., naltrexone).

Pharmacological Approach toPharmacological Approach toCocaine and Amphetamine DependenceCocaine and Amphetamine Dependence

241-4.62

• Most consistent pharmacotherapy has been obtained with tricyclic antidepressants (e.g., desipramine).

• After 1 to 2 weeks, desipramine appears to reduce craving for cocaine.

• It is postulated that the antidepressants increase functional activity in reward systems by altering cocaine-induced supersensitivity at dopamine autoreceptors.

Drugs of Abuse and How Their EffectsDrugs of Abuse and How Their EffectsMight Theoretically Be TreatedMight Theoretically Be Treated

Mechanism Main Neurotransmitter Involved Affected Potential Treatment

Action on endogenous receptors for endogenous ligandsOpioids Endorphins, enkephalins Partial agonist (e.g., buprenorphine) Antagonists (e.g., naltrexone)Alcohol GABA, endorphins Partial agonists (e.g., bretazenil)

Opiate antagonists (e.g., naltrexone)Benzodiazepines & GABA Partial agonists (e.g., bretazenil barbiturates Antagonists (e.g., flumazenil)Nicotine Acetylcholine Antagonists (? mecamylamine)Cannabinoids ? Anandamide Antagonists (e.g., SR 141716A)

LSD and related 5-HT 5-HT2 receptor antagonists hallucinogens (e.g., ritanserin)

Increasing the release of endogenous neurotransmittersCocaine Dopamine D2 receptor antagonist*

Antagonist of the uptake site (e.g., SSRI)

Solvents ? Noradrenaline ? Receptor antagonists

Antagonizing the action of natural transmittersAlcohol Glutamate NMDA antagonists (e.g., dizocilpine)

*Most typical (e.g., haloperidol) and atypical (e.g., sulpiride, tiapride, risperidone) neuroleptics have a high affinity for D2 receptors.

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Pharmacotherapy for DrugPharmacotherapy for DrugAbuse Relapse PreventionAbuse Relapse Prevention

241-4.64

Drug• Natrexone (Trexan) – opioid and alcohol

dependency• Disulfiram (Antabuse) – alcohol dependency• Clonidine (Catapres) – opioid withdrawal• Methadone (Dolophine) – opioid dependency• Buprenorphine (Buprenex) – opioid dependency• Nicotine – patches and gum• Ibogaine (Endabuse) - anticraving• Acamprosate – anti-alcohol craving• Immunization (experimental animals)

- Morphine- Cocaine

Modification of Behavior After WithdrawalModification of Behavior After Withdrawal

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Psychotherapy• Little evidence that traditional individual

psychotherapy is of value for compulsive drug user.

• Cognitive or expressive psychotherapy has improved poor prognosis patients in methadone programs.

• Special forms of group therapy and self-help groups have been demonstrated to reduce relapse.

Voluntary Groups and Self-Regulatory Communities• Alcoholic anonymous, narcotics anonymous, Phoenix

House, etc.

Supervised-Deterrent Approaches• Abstinence during a period in a hospital, prison, or

special facility followed by supervision in the community.