Neurocircuitry of Addiction: View from the Dark Side

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Neurocircuitry of Addiction View 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, G.F. and Le Moal, M. Addiction and the
anti-reward system. Annual Review of Psychology,
59 (2008)29-53 Koob, G. F. and Volkow. N. D.
Neurocircuitry of Addiction, Neuropsychopharmacolo
gy reviews 35 (2010) 217-238
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• 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

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Addiction is a Reward Deficit Disorder

• Reward neurotransmission is compromised. Brain
  reward systems are hypoactive during acute
  withdrawal, remain hypoactive with repeated
  withdrawal and during protracted abstinence.
• Anti-reward neurotransmission is recruited- Brain
  stress systems are activated during acute
  withdrawal, sensitize with repeated withdrawal
  and remain activated during protracted abstinence.

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Progression of Drug Dependence

• From Heilig M and Koob GF, Trends Neurosci,
  2007, 30399-406.

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From Koob GF, Alcohol Clin Exp Res, 2003,
27232-243.
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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)

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Stages of the Addiction Cycle
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Neurobiology of Addiction
Koob, G. F. and Volkow. N. D. Neurocircuitry of
Addiction, Neuropsychopharmacology reviews 35
(2010) 217-238
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Binge/Intoxication Stage
Koob, G. F. and Volkow. N. D. Neurocircuitry of
Addiction, Neuropsychopharmacology reviews 35
(2010) 217-238
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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.
117-143.
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Effects of 6-OHDA Lesions of the Nucleus
Accumbens on Cocaine Self-administration in Rats
From Roberts DCS, Koob GF, Klonoff P and Fibiger
HC, Pharmacol Biochem Behav, 1980, 12781-787.
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Converging Acute Actions of Drugs of Abuse on the
Ventral Tegmental Area and Nucleus Accumbens
From Nestler EJ, Nat Neurosci, 2005, 81445-1449.
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Withdrawal/Negative Affect Stage
Koob, G. F. and Volkow. N. D. Neurocircuitry of
Addiction, Neuropsychopharmacology reviews 35
(2010) 217-238
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Affective Dynamics Produced by Drug
Administration in Non Dependent versus Dependent
Subjects
From Solomon RL, American Psychologist, 1980,
35691-712.
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Reward Transmitters Implicated in the
Motivational Effects of Drugs of Abuse
Positive Hedonic Effects
Negative Hedonic Effects of Withdrawal
Dopamine dysphoria Opioid peptides ...
pain Serotonin dysphoria GABA anxiety,
panic attacks
Dopamine Opioid peptides Serotonin GABA
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Protocol for Drug Escalation
1) Initial Training Phase
2) Escalation Phase
3) Dose-Effect Study
Short Access (n12)22 x 1-hr SA session
All Rats (n24)2-hr SA sessionFixed Ratio
10.25 mg cocaine/injection
Cocaine doses (µg)0, 15.6, 31.2, 62.5,125, 250
Long Access (n12)22 x 6-hr SA session
Protocol from Ahmed SH and Koob, Science, 1998,
282298-300.
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Change in Brain Stimulation Reward Thresholds in
Long-Access (Escalation) vs. Short-Access
(Non-Escalation) Rats
From Ahmed SH, Kenny PJ, Koob GF and Markou A,
Nature Neurosci, 2002, 5625-627.
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Effect of a-flupenthixol on Cocaine
Self-Administration in Escalated and
Non-Escalated Animals
From Ahmed SH and Koob GF, unpublished results.
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Decreased Dopamine D2 Receptor Activityin a
Cocaine Abuser

• From Volkow ND, Fowler JS, Wang GJ, Hitzemann R,
  Logan J, Schlyer DJ, Dewey S and Wolf AP,
  Synapse, 1993, 14169-177.

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Affective Dynamics Produced by Drug
Administration in Non Dependent versus Dependent
Subjects
From Solomon RL, American Psychologist, 1980,
35691-712.
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Anti-Reward Transmitters Implicated in the
Motivational Effects of Drugs of Abuse
Dynorphin dysphoria CRF stress Norepinephrin
e stress
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CNS Actions ofCorticotropin-Releasing Factor
(CRF)
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Major CRF-Immunoreactive Cell Groups andFiber
Systems in the Rat Brain
From Swanson LW, Sawchenko PE, Rivier J and Vale
W, Neuroendocrinology, 1983, 36165-186.
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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
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Sampling of Interstitial Neurochemicalsby 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.

Collaborators Dr. Friedbert Weiss, Dr. Larry
Parsons, Dr. Emilio Merlo-Pich, Dr. Regina Richter
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Withdrawal-induced Increases inExtracellular
Levels of CRF
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Conditioned Place Aversion Produced by One
Pairing of Naloxone in Morphine-Dependent Rats
From Gracy KN, Dankiewicz LA and Koob GF,
Neuropsychopharmacology, 2001, 24152-160.
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CRF1 Specific Antagonists
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Effects of Antalarmin on Place Aversion Induced
by Naloxone-Precipitated Morphine Withdrawal
From Stinus L, Cador M, Zorrilla EP and Koob GF,
Neuropsychopharmacology, 2005, 3090-98.
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Competitive CRF Antagonist Injected into the
Amygdala Blocks Conditioned Place Aversionto
Opiate Withdrawal
From Heinrichs SC, Menzagi F, Schulteis G, Koob
GF and Stinus L, Behav Pharmacol, 1995, 674-80.
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Increase in Brain Reward Thresholds during
Escalation in Heroin Intake in Rats with
Prolonged Access to Heroin (23-hr/day)
From Kenny PJ, Chen SA, Markou A and Koob GF
Journal of Neuroscience 26 (2006) 5894-5900
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CRF1 Antagonist R121919 Decreases Heroin
Self-Administration in Rats with 12 h Extended
Access

• From Greenwell TN, Funk CK, Cottone P,
  Richardson HN, Chen SA, Rice K, Lee MJ, Zorrilla
  EP and Koob GF, Addict Biol, in press.

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Role of Corticotropin-releasing Factorin
Dependence
CRF antagonist effects on withdrawal-induced
anxiety-like responses
Drug
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-tetrahydrocann
abinol
? ? ? ? ?
? ? ? ? nt
? ? ? ? nt
From Koob, G.F. 2008 Neuron 5911-34
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Preoccupation/Anticipation Craving Stage
Koob, G. F. and Volkow. N. D. Neurocircuitry of
Addiction, Neuropsychopharmacology reviews 35
(2010) 217-238
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Reward Craving-Type 1

• Craving- induced by stimuli that have been
  paired with drug self-administration such as
  environmental cues
• An animal model of craving- type 1 is cue induced
  reinstatement where a cue previously paired with
  access to drug reinstates responding for a lever
  that has been extinguished.
• Neurobiological substrates include glutamatergic
  projections from medial prefrontal cortex and
  basolateral amygdala to nucleus accumbens

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Reinstatement of Drug (Alcohol) Seeking with
Drug-Associated Contextual Stimuli
Reinstatement
Daily Sessions of Self-Administration
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Role of Glutamate and Dopamine Neurotransmission
in Relapseto Drug-Seeking Behavior
From Cornish JL and Kalivas PW, J Addict Dis,
2001, 2043-54.
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Relief Craving-Type 2

• State of protracted abstinence in subjects with
  addiction or alcoholism weeks after acute
  withdrawal.
• Conceptualized as a state change characterized by
  anxiety and dysphoria or a residual negative
  emotional state that combines with Craving-Type 1
  situations to produce relapse to excessive drug
  taking
• Animal models of Craving-Type 2 include
  stress-induced reinstatement and increased drug
  taking in animals during protracted abstinence
• Neurobiological substrates include residual
  activation of brain stress systems including
  corticotropin releasing factor and norepinephrine
  in the extended amygdala

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Brain Circuits Critical for Stress-Induced
Reinstatement of Drug-Seeking Behavior
From Shaham Y, Shalev U, Lu L, De Wit H and
Stewart J, Psychopharmacology, 2003, 1683-20.
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Stress and Anti-stress Neurotransmitters
Implicated in the Motivational Effects of Drugs
of Abuse
Corticotropin-releasing factor
? ? ? ? ? ?
? ?
Neuropeptide Y
Norepinephrine
Nociceptin (orphanin FQ)
Vasopressin
Orexin (hypocretin)
Dynoprhin
Substance P
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Brain Arousal-Stress System Modulationin the
Extended Amygdala
From Koob, G.F. 2008 Neuron 5911-34
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Regulation of the Mesolimbic Dopamine Circuit and
Hypothalamus by the Extended Amygdala
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Neuroplasticity in Brain Circuits associated with
the Development of Addiction
Extended Amygdala
Compulsivity Loss of Control
Prefrontal Cortex
Dorsal Striatum
Nucleus Accumbens
Mesolimbic DA
Neuroplasticity with Increasing Use
From Koob and Volkow, Neurocircuitry of
addiction, Neuropsychopharmacology Reviews, in
press
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Allostatic Change in Emotional State associated
with Transition to Drug Addiction
Adapted from Koob GF and Le Moal M,
Neuropsychopharmacology, 2001, 2497-129.
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Key Findings and Conclusions

• Acute reinforcing effects of drugs of abuse
  depend on neurochemical substrates such as GABA,
  opioid peptides, serotonin, glutamate and
  dopamine in the ventral striatum of the basal
  forebrain.
• Acute withdrawal from all major drugs of abuse
  produces decreases in reward function, increases
  in stress-like responses and increases in CRF in
  the amygdala that are of motivational
  significance
• Craving (Preoccupation/anticipation stage of
  addiction cycle)-- involves a significant
  glutamate system dysregulation and a brain
  stress component also mediated by CRF systems in
  the extended amygdala
• 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

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Neurobiology of Drug AddictionKoob Laboratory
Visiting Professors Choon-Gon Jang Charles Heyser
Research Assistants Bob Lintz Richard
Schroeder Elena Crawford Molly Brennan Maury
Cole Tess Kimber Yanabel Grant
Administrative Assistants Lisa Maturin Mellany
Santos Marisa Gallego
Post-Doctoral Fellows Cindy Funk Brendan
Walker Tom Greenwell Sandy Ghozland Chitra
Mandyam Dong Ji Candice Contet Laura
Orio Nick Gilpin Sunmee Wee Kaushik Misra Scott
Edwards Leandro Vendruscolo
Staff Scientist Heather Richardson Olivier George
Special thanks to Mike Arends (Senior Research
Assistant)
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