Conj 556 “Addiction: Mechanisms, Prevention, Conj 556 “Addiction: Mechanisms, Prevention, Treatment”Treatment”

Charles ChavkinCharles ChavkinDepartment of PharmacologyDepartment of PharmacologyUniversity of WashingtonUniversity of Washington

>150 faculty>150 facultyMajor grants from NIAAA, NIDA, and NIMHMajor grants from NIAAA, NIDA, and NIMH

UW Centers:UW Centers: Addictive Behaviors Research CenterAlcohol and Drug Abuse InstituteCenter for Drug Addiction ResearchCenter for Functional Genomics & HCV-Related Liver DiseaseCenter for Healthcare Improvement for Addictions, Mental

Illness and Medically Vulnerable PopulationsCenter for the Study of Health & Risk BehaviorsFetal Alcohol and Drug UnitFetal Alcohol Syndrome Diagnostic & Prevention NetworkInnovative Programs Research GroupSocial Development Research Group

Societal structure and legal systemFamily structure and risky behaviors - initiation of drug useUnderserved populations at risk

College-age binge consumption, pre-addiction behaviors Co-morbid psychiatric and addictive disordersSequelae of drug abuse: teratogenesis, HIV, HepC

Molecular pharmacology of abused drugsAnimal models of addictive behavior

MACRO SCALE

INDIVIDUAL

NEURONAL

What does it mean to be a ‘broadly What does it mean to be a ‘broadly trained’ scientist studying the basis of trained’ scientist studying the basis of addiction: mechanisms, prevention & addiction: mechanisms, prevention & treatment ?treatment ?

What does it mean to be a ‘broadly What does it mean to be a ‘broadly trained’ scientist studying the basis of trained’ scientist studying the basis of addiction: addiction: mechanismsmechanisms, prevention & , prevention & treatment ?treatment ?

What are the mechanisms of addictive drug action?

How do the drugs affect the brain to produce craving and drug compulsion?

How does the underlying brain chemistry affect the response to drugs?

-- molecular and neuronal basis of behavior

What does it mean to be a ‘broadly What does it mean to be a ‘broadly trained’ scientist studying the basis of trained’ scientist studying the basis of addiction: mechanisms, addiction: mechanisms, preventionprevention & & treatment ?treatment ?What are the risk factors controlling

initiation?

What are the social factors sustaining drug use?

What are the external forces controlling relapse?

What is ‘harm reduction’, and who are ‘at-risk-youth’?

What are the social, biological and genetic factors controlling addiction risk ?

What does it mean to be a ‘broadly What does it mean to be a ‘broadly trained’ scientist studying the basis of trained’ scientist studying the basis of addiction: mechanisms, prevention & addiction: mechanisms, prevention & treatmenttreatment ? ?

How do we predict which How do we predict which interventions are likely to be interventions are likely to be effective?effective?

How do we design clinical trials How do we design clinical trials that assess treatment efficacies?that assess treatment efficacies?

What new behavioral or What new behavioral or pharmacological interventions need pharmacological interventions need to be considered?to be considered?

What is Addiction?What is Addiction? Compulsive, out-of-control Compulsive, out-of-control drug use, despite adverse consequences. Substance drug use, despite adverse consequences. Substance dependence/abuse. Specific DSM-IV criteria.dependence/abuse. Specific DSM-IV criteria.

• • Voluntary intakeVoluntary intake

EuphoriaEuphoriaToleranceTolerancePhysical dependencePhysical dependenceSensitizationSensitization

• • Involuntary - compulsive intakeInvoluntary - compulsive intake

cravings, obsession, self-cravings, obsession, self-destructive behaviordestructive behavior

AddictionAddiction

readily reversiblereadily reversible

- high relapse risk- high relapse risk

DSM-IV Criteria for Substance Dependence

A maladaptive pattern of substance use, leading to clinically significant impairment or distress, as manifested by three (or more) of the following, occurring at any time in the same 12-month period:

ToleranceWithdrawalLoss of intake control, CravingSubstance acquisition, use and recovery

consumes a major proportion of the affected person’s

time

Reduction in alternative activities

Use is continued despite objective evidence of harm

What are the goals of this course? We want you to understand the major Research themes:

Social forces that control access and initiation of drug use

Individual factors that confer vulnerability

Effective treatment options

Neurobiological effects on brain structure and function

Goals of the course con’t:Goals of the course con’t:

What does it mean to be broadly trained? Be able to intelligently discuss the question:

““What would a CURE for addiction look What would a CURE for addiction look like?”like?”

What addictive substances will we be What addictive substances will we be considering?considering?

AlcoholAlcohol

Psychostimulants (cocaine & Psychostimulants (cocaine & amphetamine)amphetamine)

Marijuana and hashishMarijuana and hashish

Opiates (heroin, morphine, oxycodone)Opiates (heroin, morphine, oxycodone)

Others:Others: nicotine, caffeine, inhalants, nicotine, caffeine, inhalants, hallucinogens, other prescription hallucinogens, other prescription drugs…drugs…

BehaviorsBehaviors: gambling, over-eating, : gambling, over-eating, sex…. sex….

Basic Pharmacology of Alcohol (ethyl Alcohol (ethyl alcohol)alcohol)

Non-potent compound: 80 mg/dL (0.08%)Non-potent compound: 80 mg/dL (0.08%)

Nonspecific compound: Nonspecific compound:

(1) Potentiates the inhibitory effects of the (1) Potentiates the inhibitory effects of the transmitter GABA by altering the conformation of transmitter GABA by altering the conformation of the heteropentameric the heteropentameric GABAGABAAA receptor receptor and increases and increases Chloride ion entry into neurons.Chloride ion entry into neurons.

(2) Inhibits the activation of (2) Inhibits the activation of NMDA-type glutamate NMDA-type glutamate receptorsreceptors reducing Sodium and Calcium ion entry reducing Sodium and Calcium ion entry into neurons.into neurons.

Basic Pharmacology of Alcohol (con’t)Alcohol (con’t)

AcuteAcute: : produces dose-dependent intoxication, loss produces dose-dependent intoxication, loss of behavioral inhibition, sedation, impaired of behavioral inhibition, sedation, impaired judgment, slurred speech, ataxia. At higher doses: judgment, slurred speech, ataxia. At higher doses: loss of consciousness, anesthesia, coma, loss of consciousness, anesthesia, coma, respiratory depression, cardiovascular depression. respiratory depression, cardiovascular depression.

ChronicChronic: hepatitis and cirrhosis, gastrointestinal : hepatitis and cirrhosis, gastrointestinal bleeding, hypertension, thiamine deficiency. bleeding, hypertension, thiamine deficiency.

TeratogenicityTeratogenicity: fetal alcohol spectrum disorders.: fetal alcohol spectrum disorders.

Major molecular pharmacological questions Major molecular pharmacological questions for Ethanol:for Ethanol:

How does its binding affect receptor functioning? Do different receptor isoforms differ in sensitivity?

How does ethanol tolerance occur?

Can a specific antagonist be designed based on an understanding of ethanol action?

Neural Systems level question:

How does ethanol activate the dopamine-reward pathways to cause changes in the brain that result in addiction?

Basic Pharmacology of PsychostimulantsBasic Pharmacology of Psychostimulants (cocaine & methamphetamine, (cocaine & methamphetamine, dextroamphetamine, methylphenidate)dextroamphetamine, methylphenidate)

Indirect acting sympathomimetics:Indirect acting sympathomimetics: block block the reuptake of the neurotransmitters: the reuptake of the neurotransmitters: dopamine, norepinephrine and serotonindopamine, norepinephrine and serotonin

Nerve terminalNerve terminal

NT reuptake

Vesicular repackaging

Vesicular fusion and transmitter release

Basic Pharmacology of PsychostimulantsBasic Pharmacology of Psychostimulants (con’t)(con’t)

AcuteAcute: arousal, euphoria, agitation, : arousal, euphoria, agitation, restlessness, insomnia, anorexia, restlessness, insomnia, anorexia, tachycardia, hyperthermia, seizures. tachycardia, hyperthermia, seizures. ChronicChronic: psychotic delusions and paranoia.: psychotic delusions and paranoia.

dopamine - euphoria, motor control, dopamine - euphoria, motor control, sexual arousalsexual arousal

norepinephrine - affect, arousal, norepinephrine - affect, arousal, euphoria, learningeuphoria, learning

serotonin - affect, appetite, sleep, serotonin - affect, appetite, sleep, sexual behavior, sexual behavior,

anxiety, painanxiety, pain

Major molecular pharmacological Major molecular pharmacological questions for Psychostimulants:questions for Psychostimulants:

How do cocaine and amphetamine affect synaptic plasticity leading to long term potentiation (LTP) and cellular events underlying learning?

How do the effects on dopamine, norepinephrine and serotonin contribute to the reinforcing and addictive effects of these drugs?

Can these insights be used to develop new therapeutics able to block or reverse the addictive effects of psychostimulants?

Basic Pharmacology of Marijuana and hashishBasic Pharmacology of Marijuana and hashish

Marijuana 9Tetrahydrocannabinol (THC) is the Active alkaloid from the cannabis plant

• Currently the most commonly used illegal drug in US

• Anandamide is the endogenous ligand

• Binds and activates abundant G-protein coupled receptors in brain (CB1 and CB2); reduces neuronal excitability by:

- increasing K+ conductance and - decreasing Ca+ + conductance

• Rimonabant (Sanofi) is a specific antagonist

Major molecular pharmacological questions Major molecular pharmacological questions for THC:for THC:

How does THC tolerance occur?

How will rimonabant or related CB1 antagonists be incorporated as therapeutics?

Neural Systems level question:

How does THC activate the dopamine-reward pathways to cause effects resulting in addiction?

Basic Pharmacology of Opiates (heroin, Basic Pharmacology of Opiates (heroin, morphine, oxycodone)morphine, oxycodone)

• Mu (Mu (), Kappa (), Kappa (), and Delta (), and Delta () type ) type opioid receptors opioid receptors

• Mu receptor activation induces Mu receptor activation induces euphoria, Kappa receptor activation euphoria, Kappa receptor activation produces dysphoria produces dysphoria

• Enkephalins, Endorphins and Dynorphins Enkephalins, Endorphins and Dynorphins are the endogenous ligands that are are the endogenous ligands that are released during stress to induce analgesia, released during stress to induce analgesia, immobility (sedation), euphoria or immobility (sedation), euphoria or dysphoria.dysphoria.

• Naloxone, Naltrexone, and Nalmefene Naloxone, Naltrexone, and Nalmefene are Mu antagonistsare Mu antagonists

• Methadone and Buprenorphine are weak Methadone and Buprenorphine are weak mu agonists used in opiate addiction mu agonists used in opiate addiction treatment.treatment.

Major molecular pharmacological questions Major molecular pharmacological questions for Opiates:for Opiates:

How does tolerance occur?

What are the mechanisms of withdrawal?

Neural Systems level question:

How does morphine activate the dopamine-reward pathways to cause changes in the brain resulting in addiction?

How does the dysphoria induced by kappa receptor activation affect the motivation to use drugs of abuse?

These are the basic ‘drug facts’ that every addiction researcher should know.

More detail: see WikipediaMore detail: see Wikipedia

Addiction is a chronic relapsing Addiction is a chronic relapsing disorder. What can we learn about the disorder. What can we learn about the molecular pharmacology of relapse?molecular pharmacology of relapse?

What are the neurobiological mechanisms What are the neurobiological mechanisms controlling relapse?controlling relapse?

Drug

Drug

consumption

consumption

timetime

escalation

escalation

crashcrash

Stress or Cue drivenStress or Cue driven

Stress releases endogenous opioids - drives Stress releases endogenous opioids - drives relapserelapseKappa opioid antagonists block stress-induced Kappa opioid antagonists block stress-induced relapserelapsebuprenorphine is a kappa antagonist.buprenorphine is a kappa antagonist.

Compulsive, out-of-control drug use, Compulsive, out-of-control drug use, despite adverse consequences.despite adverse consequences.

tolerance

withdrawalrelapse

DynorphinsDynorphins

Endogenous opioid peptides first detected in Endogenous opioid peptides first detected in early 1970’searly 1970’s1973 Goldstein first detected dynorphin in 1973 Goldstein first detected dynorphin in pituitary extractspituitary extracts1979 & 1981 Goldstein reported the sequence 1979 & 1981 Goldstein reported the sequence of dynorphin Aof dynorphin A1982 Numa cloned and sequenced the dynorphin 1982 Numa cloned and sequenced the dynorphin precursorprecursor

NeoendorphinNeoendorphin YGGFLRKYPKYGGFLRKYPKDynorphin ADynorphin A YGGFLRRIRPKLKWDNQYGGFLRRIRPKLKWDNQDynorphin BDynorphin B YGGFLRRQFKVVTYGGFLRRQFKVVT

Dynorphins act at kappa opioid receptorsDynorphins act at kappa opioid receptors

neoneo Dyn-ADyn-A Dyn-BDyn-Bsignal seqsignal seq

How do the dynorphins modulate behavior?How do the dynorphins modulate behavior?

(Pliakas et al., 2001)(Pliakas et al., 2001)

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McLaughlin et al, 2003McLaughlin et al, 2003

Forced swim stress-induced analgesia is blocked by Forced swim stress-induced analgesia is blocked by prodynorphin gene disruptionprodynorphin gene disruption

Dynorphin is a stress hormone; stress affects drug abuse risk; how does dynorphin release affect cocaine reward?

Day: 1 2 3 4 5 6

Preference test, 30 min

Cocaine conditioning, 30 min

Vehicle conditioning, 30 min

Forced swim stress exposure

McLaughlin et al, 2003McLaughlin et al, 2003

Forced swim stress potentiation of cocaine conditioned-place Forced swim stress potentiation of cocaine conditioned-place preference (CPP) mediated by endogenous dynorphinspreference (CPP) mediated by endogenous dynorphins

Prodynorphin gene knockoutProdynorphin gene knockout

Similar block Similar block with KOR-/-with KOR-/-

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Extinction Footshock Cocaine PrimeExtinction Footshock Cocaine Prime

preference

Redila, unpublished observationsRedila, unpublished observations

Kappa opioid receptor activation by Kappa opioid receptor activation by endogenous dynorphins during endogenous dynorphins during repeated repeated forced swim, chronic social stress, forced swim, chronic social stress, footshock, and chronic painfootshock, and chronic pain produces: produces:

• • Stress-induced immobilityStress-induced immobility

• • Stress-induced analgesiaStress-induced analgesia

• • Stress-induced potentiation of Stress-induced potentiation of cocaine-CPPcocaine-CPP

• • Stress-induced reinstatement of Stress-induced reinstatement of cravingcraving

• • blocked by norBNI, prodyn-/-, blocked by norBNI, prodyn-/-, KOR-/-KOR-/-

Since KOR activation produces dysphoria Since KOR activation produces dysphoria in humans and aversion in rodents, how in humans and aversion in rodents, how does it potentiate reward mechanisms?does it potentiate reward mechanisms?

Pre cocainePost cocaine

m is the hypothetical rewarding valence of cocainem is the hypothetical rewarding valence of cocaine

Mood state

Mood state

StressedStressed Normal Normal

m

m

(DA, NE + 5HT?)(DA, NE + 5HT?)

Hypothetical model to explain negative reinforcement Hypothetical model to explain negative reinforcement prior to cocaine trainingprior to cocaine training

U50488 (5mg/kg) cocaine (15 mg/kg)

timetime cppcpp

Kappa receptor activation prior to cocaine potentiatesKappa receptor activation prior to cocaine potentiates

(McLaughlin et al, 2006)(McLaughlin et al, 2006)

Does swim stress create KOR dependent Does swim stress create KOR dependent dysphoria?dysphoria?

Cannot use classical CPA conditioning because Cannot use classical CPA conditioning because of the swimof the swim

Pair swim with a smell (olfactory cue); test in a Pair swim with a smell (olfactory cue); test in a different environment with access to smelldifferent environment with access to smell

Olfactory cueOlfactory cue

Where in the brain are dynorphins Where in the brain are dynorphins acting to produce their behavioral acting to produce their behavioral effects? effects? (how is the stress-circuit (how is the stress-circuit organized?)organized?)

What cell types mediate the effects, What cell types mediate the effects, (immunohistochemistry)(immunohistochemistry)

What signal transduction mechanisms are What signal transduction mechanisms are involved, andinvolved, and

How is the processing within the How is the processing within the neuronal circuit neuronal circuit

affected? affected? (electrophysiology)(electrophysiology)

Activated kappa opioid receptors are Activated kappa opioid receptors are phosphorylated at serine-369 by G-protein phosphorylated at serine-369 by G-protein receptor kinase. receptor kinase. Phosphoselective antibody KOR-P developed Phosphoselective antibody KOR-P developed to identify sites of dynorphin action in to identify sites of dynorphin action in brain.brain.

Increased KOR-P in GFAP-ir astrocytes and GABAergic neuronsin nAcc

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Behavioral stress (forced swim, social Behavioral stress (forced swim, social defeat, neuropathic pain) induce defeat, neuropathic pain) induce dynorphin release and KOR dynorphin release and KOR activation following CRF-R2 activation following CRF-R2 receptor activation.receptor activation.

Dynorphin/KOR activation seems to Dynorphin/KOR activation seems to encode the aversive (dysphoric) encode the aversive (dysphoric) component of chronic stress by component of chronic stress by p38 MAPK activation. p38 MAPK activation.

Stress/CRF activates dynorphin-KOR Stress/CRF activates dynorphin-KOR systems broadly in the CNSsystems broadly in the CNS

Therapeutically, KOR antagonism may Therapeutically, KOR antagonism may potentially reduce stress-induced potentially reduce stress-induced addictive drug craving and reduce addictive drug craving and reduce relapse risk.relapse risk.

Thanks:Thanks:

Jay McLaughlinJay McLaughlin Mike Bruchas Mike BruchasBen Land Ben Land Shuang LiShuang LiMei XuMei Xu Megumi AitaMegumi AitaVan RedilaVan Redila Dan MessingerDan MessingerJulia LemosJulia Lemos Erica MeliefErica Melief