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Neurobiology of Addiction: Shedding Light from the Dark
Side
George F. Koob, Ph.D. Professor and Chair Committee on the
Neurobiology of Addictive Disorders The Scripps Research Institute
La Jolla, California Koob GF. The neurobiology of addiction: a
neuroadaptational view relevant for diagnosis. Addiction, 2006,
101(suppl 1):23-30. Koob GF, Le Moal M. Addiction and the
anti-reward system. Annual Review of Psychology, 2008, 59:29-53.
Koob GF. A role for brain stress systems in addiction. Neuron,
2008, 59:11-34. 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 Key Findings and Conclusions
Addiction loss of control over drug intake and compulsive drug
taking driven by elements of impulsivity and compulsivity that are
mediated by separate but overlapping neurocircuitry Acute rewarding
effects of drugs of abuse are mediated by neurochemical elements
such as dopamine and opioid peptides in the nucleus accumbens and
amygdala Acute withdrawal from all major drugs of abuse produces
increases in reward thresholds, increases in anxiety-like responses
and increases in CRF in the amygdala that are of motivational
significance Compulsive drug use associated with dependence is
mediated by not only loss of function of reward systems but
recruitment of brain stress systems such as corticotropin releasing
factor, norepinephrine and dynorphin in the extended amygdala
Brain-arousal stress systems in the extended amygdala--- may be key
components of not only for the negative emotional states that drive
dependence on drugs of abuse but also may overlap with the negative
emotional components of other psychopathologies Neurocircuitry of
Addiction
KoobG/CNAD/dia1/090808jh Derived from:Koob G, Everitt, Band Robbins
T,Reward, motivation, and addiction. In: Squire LR, Berg D, Bloom
FE, du Lac S, Ghosh A, Spitzer NC (Eds.), Fundamental Neuroscience,
3rd edition, Academic Press, Amsterdam, 2008, pp Key Common
Neuroanatomical Structures in Addiction
Nucleus Accumbens and Central Nucleus of theAmygdala Forebrain
structures involved in the rewarding effects of drugs of abuse and
drives the binge intoxication stage of addiction.Contains key
reward neurotransmitters: dopamine and opioid peptides Extended
Amygdala 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. Contains brain stress neurotransmitter,
corticotropin releasing factor that controls hormonal, sympathetic,
and behavioral responses to stressors, and is involved in the
anti-reward effects of drug dependence Medial Prefrontal Cortex
neurobiological substrate for executive function that is
compromised in drug dependence and plays a key role in facilitating
relapse. Contains major glutamatergic projection to nucleus
accumbens and amygdala Neurocircuitry of Addiction
KoobG/CNAD/dia1/090808jh Derived from:Koob G, Everitt, Band Robbins
T,Reward, motivation, and addiction. In: Squire LR, Berg D, Bloom
FE, du Lac S, Ghosh A, Spitzer NC (Eds.), Fundamental Neuroscience,
3rd edition, Academic Press, Amsterdam, 2008, pp
KoobG/NP/dia3/031902jh From: Koob GF, Alcohol Clin Exp Res, 2003,
27: Positive and Negative Reinforcement- Definitions
Positive Reinforcement defined as the process by which presentation
of a stimulus (drug)increases the probability of a response (non
dependent drug taking paradigms). Negative Reinforcement defined as
a process by which removal of an aversive stimulus (negative
emotional state of drug withdrawal) increases the probability of a
response (dependence-induced drug taking) Stages of the Addiction
Cycle
KoobG/NP/dia2/051605jh 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
008KoobG/NP/sca3c/011000jh.psd Cocaine Self-Administration
Was: KoobG/NP/dia1/060899jh Became: KoobG/NP/dia2/092502jh
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
KoobG/NP/dia6/041204jh From:Koob GF, Clin Neurosci Res, 2005, 5:
KoobG/NP/sca1/030104jh Pieter Bruegel Protocol for Initiation of
Lever Pressing for Oral Ethanol Self-Administration in the
Rat
Rats trained to lever press on a FR-1 schedule % saccharin Ethanol
added to the saccharin solution Access to ethanol and water or
ethanol or saccharin and water KoobG/NP/gra1/050202jh Initiation of
the free-choice operant task: ethanol (10%) and water From:
Rassnick S, Pulvirenti L and Koob GF, Alcohol, 1993, 10: Effects of
Methylnaloxonium on Ethanol Self-Administration in Non-Dependent
Rats
KoobG/NP/gra3/110304jh From: Heyser CJ, Roberts AJ, Schulteis G and
Koob GF, Alcohol Clin Exp Res, 1999, 23: Converging Acute Actions
of Drugs of Abuse on the Ventral Tegmental Area and Nucleus
Accumbens
KoobG/MIND/dia1/053006jh From: Nestler EJ, Nat Neurosci, 2005, 8:
no# ppt: Svayasamin Standard Pattern of Affective Dynamics Produced
by Novel and Repeated Unconditioned Stimulus
KoobG/MIND/gra9/013106jh From: Solomon RL, American Psychologist,
1980, 35: Mood Changes Associated with Plasma Levels of Cocaine
During Coca Paste Smoking
KoobG/MIND/gra4/020706jh From: Van Dyke C and Byck R, Cocaine,
Scientific American, 1982, 246: Protocol for Drug Escalation
1) Initial Training Phase 2) Escalation Phase 3) Testing Phase
Short Access22 x 1-hr SA session All Rats1-hr SA session Fixed
Ratio mg cocaine/injection Neuropharmacological probes Long
Access22 x 6-hr SA session KoobG/NP/wor1/030104jh Protocol from:
Ahmed SH and Koob, Science, 1998, 282: Change in Brain Stimulation
Reward Thresholds in Long-Access (Escalation) vs. Short-Access
(Non-Escalation) Rats KoobG/MIND/gra13/013106jh From: Ahmed SH,
Kenny PJ, Koob GF and Markou A, Nature Neurosci, 2002, 5:
Progressive-ratio Responding for Cocaine in Long- and Short-access
Rats
KoobG/CNAD/gra5/041108jh From:Wee S, Mandyam CD, Lekic DM and Koob
GF, Eur Neuropsychopharmacol, 2008, 18: Effect of a-flupenthixol on
Cocaine Self-Administration in Escalated and Non-Escalated
Animals
KoobG/NP/gra1/061103jh From: Ahmed SH and Koob GF,
Psychopharmacology, 2004, 172: Escalation of Methamphetamine
Self-administration in Rats
KoobG/CNAD/gra1/052907jh Adapted from: Wee S, Wang Z, Woolverton
WL, Pulvirenti L and Koob GF, Neuropsychopharmacology, 2007, 32:
Effects of Aripiprazole on Methamphetamine Self-administration
(0
Effects of Aripiprazole on Methamphetamine Self-administration
(0.05 mg/kg/inf progressive-ratio) KoobG/CNAD/gra10/100407jh
Adapted from:Wee S, Wang Z, Woolverton WL, Pulvirenti L and Koob
GF, Neuropsychopharmacology, 2007, 32: Sampling of Interstitial
Neurochemicals by in vivo Microdialysis
Allows sampling of neurochemicals inconscious animals (correlate
brainchemistry with behavior). Implanted so that
semi-permeableprobe tip is in specific brain region ofinterest.
Substances below the membrane MWcutoff diffuse across membrane
basedon concentration gradient. Both neurochemical sampling
andlocalized drug delivery are possible. Collaborators: Dr.
Friedbert Weiss, Dr. Larry Parsons, Dr. Emilio Merlo-Pich, Dr.
Regina Richter Extracellular DA and 5-HT in the Nucleus Accumbens
During Cocaine Self-Administration and Withdrawal
KoobG/NP/gra1/010302jh From: Parsons LH, Koob GF and Weiss F, J
Pharmacol Exp Ther, 1995, 274: Decreased Dopamine D2 Receptor
Activity in a Cocaine Abuser
no# ppt: volkow d2 activity From:Volkow ND, Fowler JS, Wang GJ,
Hitzemann R, Logan J, Schlyer DJ, Dewey S and Wolf AP, Synapse,
1993, 14: Negative Hedonic Effects
Reward Transmitters Implicated in the Motivational Effects of Drugs
of Abuse Positive Hedonic Effects Negative Hedonic Effects of
Withdrawal Dopamine Opioid peptides Serotonin GABA Dopamine
dysphoria Opioid peptides ... pain Serotonin dysphoria GABA
anxiety, panic attacks KoobG/NP/wor2/030104jh Standard Pattern of
Affective Dynamics Produced by Novel and Repeated Unconditioned
Stimulus
KoobG/MIND/gra9/013106jh From: Solomon RL, American Psychologist,
1980, 35: Anti-Reward Transmitters Implicated in the Motivational
Effects of Drugs of Abuse
Dynorphin dysphoria CRF stress Norepinephrine stress NPY
anti-stress KoobG/NP/wor2/030104jh CNS Actions of
Corticotropin-Releasing Factor (CRF)
KoobG/NP/dia2/011000jh Major CRF-Immunoreactive Cell Groups and
Fiber Systems in the Rat Brain
KoobG/NP/dia1/061499jh From: Swanson LW, Sawchenko PE, Rivier J and
Vale W, Neuroendocrinology, 1983, 36: CRF Produces Arousal,
Stress-like Responses, and a Dysphoric, Aversive State
Paradigm CRF Agonist CRF Antagonist Acoustic startle Facilitates
startle Blocks fear-potentiated startle Elevated plus maze
Suppresses exploration Reverses suppression of exploration
Defensive burying Enhances burying Reduces burying Fear
conditioning Induces conditioned fear Blocks acquisition of
conditioned fear Cued electric shock Enhances freezing Attenuates
freezing Taste / Place Conditioning Produces place aversion Weakens
drug-induced place aversion no# ppt: crfagon/antagon text Sampling
of Interstitial Neurochemicals by in vivo Microdialysis
Allows sampling of neurochemicals inconscious animals (correlate
brainchemistry with behavior). Implanted so that
semi-permeableprobe tip is in specific brain region ofinterest.
Substances below the membrane MWcutoff diffuse across membrane
basedon concentration gradient. Both neurochemical sampling
andlocalized drug delivery are possible. Collaborators: Dr.
Friedbert Weiss, Dr. Larry Parsons, Dr. Emilio Merlo-Pich, Dr.
Regina Richter Withdrawal-induced Increases in Extracellular Levels
of CRF
KoobG/CNAD/gra1c/020608jh Rodent model of excessive drinking during
withdrawal(Roberts et al 1996, 2000; ODell et al 2004)
Self-administration training Sweetened solution fading used to
train animals to lever press for: 10%w/v EtOHvsWater Chronic
intermittent alcohol vapors (4+ wks) Target blood alcohol levels
(BALs): g% Dependence induction Withdrawal from alcohol vapors
Negative emotional state: Anxiety-like behavior Reward threshold
deficits Increased CRF release in the extended amygdala Excessive
drinking: 2-3 fold higher alcohol intake Increased progressive
ratio breakpoints Relapse following prolonged abstinence Enhanced
Ethanol Self-Administration During Withdrawal in Dependent
Animals
*** *** KoobG/NP/gra1/121305jh n = 6/group *p < vs.
Nondependent-EtOH From: Funk C and Koob GF, unpublished results. 40
CRF1 Specific Antagonists MPZP
KoobG/CNAD/gra1/100807jh From:Richardson HN, Zhao Y, Fekete EM,
Funk CK, Wirsching P, Janda KD, Zorrilla EP and Koob GF, Pharmacol
Biochem Behav, 2008, 88: Effect of CRF Antagonist D-Phe-CRF12-41
Central Nucleus of the Amygdala
KoobG/MIND/gra1/013106jh From: Funk C, ODell LE and Koob GF, J
Neurosci, 2006, 26: 1941 Good Housekeeping Total 23 h Active and
Inactive Responding after Repeated 72 h Nicotine Deprivation Cycles
Followed by 4 Days of Self-administration KoobG/CNAD/gra5/100407jh
From:George O, Ghozland S, Azar MR, Cottone P, Zorrilla EP, Parsons
LH, ODell LE, Richardson HN and Koob GF, Proc Natl Acad Sci USA,
2007, 104: Effect of CRF1 Antagonism on Nicotine
Self-administration in Rats with Extended Access
KoobG/CNAD/gra3/100407jh From:George O, Ghozland S, Azar MR,
Cottone P, Zorrilla EP, Parsons LH, ODell LE, Richardson HN and
Koob GF, Proc Natl Acad Sci USA, 2007, 104: CRF1 Antagonist has No
Effect on Baseline Responding for Nicotine in Rats with Unlimited
Access
KoobG/CNAD/gra1/100407jh From:George O, Ghozland S, Azar MR,
Cottone P, Zorrilla EP, Parsons LH, ODell LE, Richardson HN and
Koob GF, Proc Natl Acad Sci USA, 2007, 104: Role of
Corticotropin-releasing Factor in Dependence
Drug CRF antagonist effects on withdrawal-induced anxiety-like
responses Withdrawal-induced changes in extracellular CRF in CeA
CRF antagonist effects on dependence-induced increases in
self-administration CRF antagonist reversal of stress-induced
reinstatement Cocaine Opioids Ethanol Nicotine
9-tetrahydrocannabinol * nt nt KoobG/CNAD/wor2/021908jh.ppt retyped
= aversive effects with place conditioning. nt = not tested. CeA =
central nucleus of the amygdala. * Non-dependent Dependent
Positive Reinforcement Negative Non-dependent Dependent Negative
Reinforcement Positive KoobG/CNAD/dia3/030607jh animated Stress and
Anti-stress Neurotransmitters Implicated in the Motivational
Effects of Drugs of Abuse
Corticotropin-releasing factor Neuropeptide Y Norepinephrine
Nociceptin (orphanin FQ) Vasopressin KoobG/NP/wor2/030104jh Orexin
(hypocretin) Dynoprhin Brain Arousal-Stress System Modulation in
the Extended Amygdala
KoobG/CNAD/dia9b/012508jh Pain, Emotions, and the Amygdala
KoobG/CNAD/dia3/021408jh From: Neugebauer V, Li W, Gird GC and Han
JS, The Neuroscientist, 2004, 10: Allostatic Change in Mood State
associated with Transition to Drug Addiction
KoobG/NP/dia4/053102jh Adapted from: Koob GF and Le Moal M,
Neuropsychopharmacology, 2001, 24: Key Findings and
Conclusions
Addiction loss of control over drug intake and compulsive drug
taking driven by elements of impulsivity and compulsivity that are
mediated by separate but overlapping neurocircuitry Acute rewarding
effects of drugs of abuse are mediated by neurochemical elements
such as dopamine and opioid peptides in the nucleus accumbens and
amygdala Acute withdrawal from all major drugs of abuse produces
increases in reward thresholds, increases in anxiety-like responses
and increases in CRF in the amygdala that are of motivational
significance Compulsive drug use associated with dependence is
mediated by not only loss of function of reward systems but
recruitment of brain stress systems such as corticotropin releasing
factor, norepinephrine and dynorphin in the extended amygdala
Brain-arousal stress systems in the extended amygdala--- may be key
components of not only for the negative emotional states that drive
dependence on drugs of abuse but also may overlap with the negative
emotional components of other psychopathologies Neurobiology of
Drug Addiction Koob Laboratory
Postdoctoral Fellows Nick Gilpin Sunmee Wee Laura Orio Kaushik
Misra Scott Edwards Candice Contet Cindy Funk Brendan Walker Tom
Greenwell Sandy Ghozland Chitra Mandyam Dong Ji Research Assistants
Bob Lintz Richard Schroeder Elena Crawford Molly Brennan Maury Cole
Tess Kimber Yanabel Grant Administrative Assistants Lisa Maturin
Mellany Santos Marisa Gallego Staff Scientists Olivier George Bob
Purdy Heather Richardson Special thanks: Mike Arends (Senior
Research Assistant) Janet Hightower (TSRI Biomedical Graphics) TSRI
Chemists Kim Janda Tobin Dickerson Ed Roberts
KoobG/NP/wor1/070902jh Support from: Pearson Center for Alcoholism
and Addiction Research National Institute on Alcohol Abuse and
Alcoholism National Institute on Drug Abuse National Institute of
Diabetes and Digestive and Kidney Diseases