The Neuroscience of Addiction George F. Koob, Ph.D. Professor and Chairman Committee on the Neurobiology of Addictive Disorders The Scripps Research Institute La Jolla, California

Cost and Scope of Addiction Alcohol –18 million Americans abuse or are dependent on Alcohol. 2.2 million - approximately 10% currently seek treatment Cost to society estimated at $185B/year Smoking --In US, approximately 440,000 persons die per year of a cigarette smoking- attributable illness This is approx. $75 billion in direct medical costs, and $82 billion in lost productivity/year Opioid Dependency –Dependency has been growing rapidly: From 1990 to 2001, the number of people who used prescription painkillers recreationally for the first time grew by 335% to include almost 2.5 million people. Over an 8-year period ( ): Admissions involving oxycodone rose 450% Admissions involving hydrocodone rose 170%

Estimated Prevalence Among Year Olds of Nonmedical Use and Dependence Among Users ( ) (NCS) Tobacco Alcohol Illicit Drugs Cannabis Cocaine Stimulants Anxiolytics Analgesics Psychedelics Heroin Inhalants Ever Used Prevalence of Dependence Dependence Among Users From: Anthony JC, Warner LA and Kessler RC, Exp Clin Psychopharmacol, 1994, 2:

The San Diego Union-Tribune Thursday, August 30, 2001

Key Definitions Drug Addiction — Chronically relapsing disorder that is characterized by a compulsion to seek and take drug, loss of control in limiting intake, and emergence of a negative emotional state (e.g. dysphoria, anxiety, irritability) when access to the drug is prevented (here, defined as the “dark side” of addiction) Nucleus Accumbens and Extended Amygdala — Forebrain structures involved in the rewarding effects of drugs of abuse. Composed of central nucleus of the amygdala, bed nucleus of the stria terminalis, and a transition zone in the medial part of the nucleus accumbens Corticotropin-Releasing Factor — “brain stress” neurotransmitter, 41 amino acid polypeptide that controls hormonal, sympathetic, and behavioral responses to stressors Transcription Factors — brain chemicals involved in the longterm neuroadaptive changes within neurocircuits associated with chronic administration of drugs of abuse. Transcription factors can gene expression

“When people talk about drugs, they assume people take drugs because they enjoy it,” Williams told the Toronto Star. “But really, it's no different from overeating or watching too much television or drinking too much. You take drugs to make yourself feel better, to fill a hole.” -Ricky Williams -Byline Damien Cox, Toronto Star, May 29, 2006

From: Koob GF, Alcohol Clin Exp Res, 2003, 27:

Stages of the Addiction Cycle

Animal Models for the Different Stages of the Addiction Cycle Animal Models for the Binge/Intoxication Stage 1. Oral or intravenous drug self-administration 2. Brain stimulation reward 3. Place preference Animal models for the Withdrawal/Negative Affect Stage 1. Brain stimulation reward 2. Place aversion Animal Models for the Transition to Addiction 1. Dependence-induced drug taking 2. Escalation in drug self-administration with prolonged access 3. Drug taking despite aversive consequences Animal Models for the Preoccupation/Anticipation (“Craving”) Stage 1. Drug- induced reinstatement 2. Cue- induced reinstatement 3. Alcohol Deprivation Effect 4. Stress- induced reinstatement

Mood Changes Associated with Plasma Levels of Cocaine during Coca Paste Smoking From: Van Dyke C and Byck R, Cocaine, Scientific American, 1982, 246:

Cocaine Self-Administration From:Caine SB, Lintz R and Koob GF. in Sahgal A (ed) Behavioural Neuroscience: A Practical Approach, vol. 2, IRL Press, Oxford, 1993, pp

Neurochemical Circuitry in Drug Reward

Neurobiological Substrates for the Acute Reinforcing Effects of Drugs of Abuse Neurotransmitter Dopamine Opioid Peptides GABA Glutamate Site Ventral tegmental area, nucleus accumbens Nucleus accumbens, amygdala, ventral tegmental area Amygdala, bed nucleus of stria terminalis Nucleus accumbens

Converging Acute Actions of Drugs of Abuse on the Ventral Tegmental Area and Nucleus Accumbens From: Nestler EJ, Nat Neurosci, 2005, 8:

Reward Transmitters Implicated in the Positive Motivational Effects of Drugs of Abuse Dopamine Opioid peptides GABA Glutamate Serotonin Positive Hedonic Effects

From: Solomon RL and Corbit JD, Psychol Rev, 1974, 81:

Sampling of Interstitial Neurochemicals by in vivo Microdialysis Allows sampling of neurochemicals in conscious animals (correlate brain chemistry with behavior). Implanted so that semi-permeable probe tip is in specific brain region of interest. Substances below the membrane MW cutoff diffuse across membrane based on concentration gradient. Both neurochemical sampling and localized drug delivery are possible.

Extracellular DA and 5-HT in the Nucleus Accumbens During Cocaine Self-Administration and Withdrawal From: Parsons LH, Koob GF and Weiss F, J Pharmacol Exp Ther, 1995, 274:

Reward Transmitters Implicated in the Motivational Effects of Drugs of Abuse Dopamine … “dysphoria” Opioid peptides... pain Serotonin … “dysphoria” GABA … anxiety, panic attacks Dopamine Opioid peptides Serotonin GABA Positive Hedonic EffectsNegative Hedonic Effects of Withdrawal

Potential Substrates in the Extended Amygdala for the Motivational Effects of Drug Dependence Heimer L and Alheid G, Piecing together the puzzle of basal forebrain anatomy. In: Napier TC, Kalivas PW and Hanin I (Eds), The Basal Forebrain: Anatomy to Function (series title: Advances in Experimental Medicine and Biology, Vol. 295), Plenum Press, New York, 1991, pp Modified from:

Pieter Bruegel

CNS Actions of Corticotropin Releasing Factor (CRF)

Major CRF-IR Cell Groups and Fiber Systems Illustrated Schematically in a Sagittal View of the Rat Brain From: Swanson LW, Sawchenko PE, Rivier J and Vale W, Neuroendocrinology, 1983, 36:

CRF Produces Arousal, Stress-like Responses, and a Dysphoric, Aversive State ParadigmCRF AgonistCRF Antagonist Acoustic startle Facilitates startleBlocks fear-potentiated startle Elevated plus maze Suppresses explorationReverses suppression of exploration Defensive burying Enhances buryingReduces burying Fear conditioning Induces conditioned fearBlocks acquisition of conditioned fear Cued electric shock Enhances freezingAttenuates freezing Taste / Place Conditioning Produces place aversionWeakens drug-induced place aversion

Protocol for Initiation of Lever Pressing for Oral Ethanol Self-Administration in the Rat Initiation of the free-choice operant task: ethanol (10%) and water Rats trained to lever press on a FR-1 schedule Ethanol added to the saccharin solution Access to ethanol and water or ethanol + saccharin and water Days Day Days Day Days Day 0.2% - 0.2% - 0.2% - 0.2% - 0% 5% 8% 10% ******** TrainingSaccharin (w/v)EtOH (w/v)

Ethanol Dependence Induction From: Rassnick S, Heinrichs SC, Britton KT and Koob GF, Brain Res, 1993, 605: From: Rogers J, Wiener SG and Bloom FE, Behav Neural Biol, 1979, 27:

The AWOL System (Alcohol WithOut Liquid) Patented by Spirit Partners, Inc. Available as 1, 2, or 4 user machines (cost $299 to $2845). Legal in U.S. Consists of oxygen generator and hand-held vaporizer. 80-proof alcohol (40% alcohol by volume) is poured into vaporizer, and vapor is inhaled.

Extracellular CRF Levels in the Central Amygdala During Ethanol Withdrawal

Effect of CRF Antagonist D -Phe-CRF – Central Nucleus of the Amygdala – From: Funk C, O’Dell LE and Koob GF, Journal of Neuroscience, 2006, 44:

Neurotransmitters Implicated in the Motivational Effects of Withdrawal from Drug of Abuse Dopamine … “dysphoria” Serotonin … “dysphoria” GABA … anxiety, panic attacks NPY … anti-stress Dynorphin … “dysphoria” CRF … stress Norepinephrine … stress Glutamate….hyperexcitability

Neurochemical Changes Associated with the Transition from Drug Use to Dependence From:Roberts AJ and Koob GF, Alcohol: ethanol antagonists/amethystic agents. in Adelman G and Smith BH (Eds.), Encyclopedia of Neuroscience, 3rd edn, Elsevier, New York, 2003 [

Craving-Type 1 “Craving”- induced by stimuli that have been paired with ethanol self-administration such as environmental cues Termed conditioned positive reinforcement in experimental psychology An animal model of craving- type 1 is cue induced reinstatement where a cue previously paired with access to ethanol reinstates responding for a lever that has been extinguished.

Craving-Type 2 State of protracted abstinence in alcoholics weeks after acute withdrawal Conceptualized as a state change characterized by anxiety and dysphoria or a residual negative affective state that combines with Craving-Type 1 situations to produce relapse to excessive drinking Animal models of Craving-Type 2 include stress-induced reinstatement, or increased drinking in animals after a prolonged deprivation (Alcohol Deprivation Effect)

Reinstatement Neurobiological Effects of Exposure to Drug-Associated Contextual Stimuli SAEXT S - S+S+ Daily Sessions of Self-Administration

Effects of D-Phe-CRF and Naltrexone on Stress- and Cue-Induced Reinstatement of Ethanol-Seeking Liu & Weiss (2002) J Neurosci

Neurochemical Changes Associated with the Drug Use, Dependence and Relapse

Common Molecular Changes Associated with Dependence Dopamine D-2 receptor binding- decreased in human imaging studies in dependent subjects CREB ( cyclic adenosine monophosphate response element binding protein) transcription factor- decreased in nucleus accumbens and extended amygdala during the development of dependence Delta-FosB transcription factor-changed during protracted abstinence to drugs of abuse

Key Common Neurocircuitry Elements in Drug Seeking Behavior of Addiction

Summary- Neurocircuitry of Addiction Reward Circuit- nucleus accumbens and extended amygdala (bed nucleus of the stria terminalis and central nucleus of the amygdala) “Craving” Circuit- dorsal prefrontal cortex, basolateral amygdala “Compulsivity” Circuit- ventral striatum, ventral pallidum,medial thalamic- orbitofrontal cortical loop

Medications for Alcohol Dependence Disulfiram (Antabuse) - FDA approved 1954 Naltrexone (ReVia) - FDA approved 1994 Acamprosate - FDA approved 2004

Effects of Drugs on Animal Models of Different Components of the Addiction Cycle Relevant for Medications Development NaltrexoneAcamprosate CRF Antagonist NMDA/ GABA Allosteric Modulator Orphanin FQ / Nociceptin Agonist mGluR Group II Agonist Baseline Drinking  ——  —— Dependence- Induced drinking  Cue-Induced Reinstatement  —  Stress-Induced Reinstatement —  ADE / Protracted Abstinence 

Medications Development

Support from: National Institute on Alcohol Abuse and Alcoholism National Institute on Drug Abuse National Institute of Diabetes and Digestive and Kidney Diseases Pearson Center for Alcoholism and Addiction Research