1. 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, Neuropsychopharmacology reviews 35 (2010)

2. “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

3. 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.

4. Progression of Drug Dependence
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From: Heilig M and Koob GF, Trends Neurosci, 2007, 30:

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

6. 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)

7. Stages of the Addiction Cycle
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8. Neurobiology of Addiction
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Koob, G. F. and Volkow. N. D. Neurocircuitry of Addiction, Neuropsychopharmacology reviews 35 (2010)

9. Binge/Intoxication Stage
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Koob, G. F. and Volkow. N. D. Neurocircuitry of Addiction, Neuropsychopharmacology reviews 35 (2010)

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

11. Effects of 6-OHDA Lesions of the Nucleus Accumbens on Cocaine Self-administration in Rats
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From: Roberts DCS, Koob GF, Klonoff P and Fibiger HC, Pharmacol Biochem Behav, 1980, 12:

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

13. no# ppt: Svayasamin

14. Withdrawal/Negative Affect Stage
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Koob, G. F. and Volkow. N. D. Neurocircuitry of Addiction, Neuropsychopharmacology reviews 35 (2010)

15. Affective Dynamics Produced by Drug Administration in Non Dependent versus Dependent Subjects
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From: Solomon RL, American Psychologist, 1980, 35:

16. 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
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17. Protocol for Drug Escalation
1) Initial Training Phase
2) Escalation Phase
3) Dose-Effect Study
Short Access (n=12) 22 x 1-hr SA session
All Rats (n=24): 2-hr SA session Fixed Ratio mg cocaine/injection
Cocaine doses (µg): 0, 15.6, 31.2, 62.5, 125, 250
Long Access (n=12) 22 x 6-hr SA session
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Protocol from: Ahmed SH and Koob, Science, 1998, 282:

18. Change in Brain Stimulation Reward Thresholds in Long-Access (Escalation) vs. Short-Access (Non-Escalation) Rats
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From: Ahmed SH, Kenny PJ, Koob GF and Markou A, Nature Neurosci, 2002, 5:

19. Effect of a-flupenthixol on Cocaine Self-Administration in Escalated and Non-Escalated Animals
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From: Ahmed SH and Koob GF, unpublished results.

20. 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:

21. Affective Dynamics Produced by Drug Administration in Non Dependent versus Dependent Subjects
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From: Solomon RL, American Psychologist, 1980, 35:

22. Anti-Reward Transmitters Implicated in the Motivational Effects of Drugs of Abuse
Dynorphin … “dysphoria”
CRF … stress
Norepinephrine … stress
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23. CNS Actions of Corticotropin-Releasing Factor (CRF)
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24. Major CRF-Immunoreactive Cell Groups and Fiber Systems in the Rat Brain
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From: Swanson LW, Sawchenko PE, Rivier J and Vale W, Neuroendocrinology, 1983, 36:

25. 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: crf agon/antagon text

26. 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.
Collaborators: Dr. Friedbert Weiss, Dr. Larry Parsons, Dr. Emilio Merlo-Pich, Dr. Regina Richter

27. Withdrawal-induced Increases in Extracellular Levels of CRF
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29. Conditioned Place Aversion Produced by One Pairing of Naloxone in Morphine-Dependent Rats
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From: Gracy KN, Dankiewicz LA and Koob GF, Neuropsychopharmacology, 2001, 24:

30. CRF1 Specific Antagonists
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31. Effects of Antalarmin on Place Aversion Induced by Naloxone-Precipitated Morphine Withdrawal
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From: Stinus L, Cador M, Zorrilla EP and Koob GF, Neuropsychopharmacology, 2005, 30:90-98.

32. Competitive CRF Antagonist Injected into the Amygdala Blocks Conditioned Place Aversion to Opiate Withdrawal
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From: Heinrichs SC, Menzagi F, Schulteis G, Koob GF and Stinus L, Behav Pharmacol, 1995, 6:74-80.

33. Increase in Brain Reward Thresholds during Escalation in Heroin Intake in Rats with Prolonged Access to Heroin (23-hr/day)
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From: Kenny PJ, Chen SA, Markou A and Koob GF Journal of Neuroscience 26 (2006)

34. CRF1 Antagonist R121919 Decreases Heroin Self-Administration in Rats with 12 h Extended Access
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From: Greenwell TN, Funk CK, Cottone P, Richardson HN, Chen SA, Rice K, Lee MJ, Zorrilla EP and Koob GF, Addict Biol, in press. 34

35. 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
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retyped
= aversive effects with place conditioning. nt = not tested. CeA = central nucleus of the amygdala. *
From: Koob, G.F Neuron 59:11-34

36. 023scan.tif

37. Preoccupation/Anticipation “Craving” Stage
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Koob, G. F. and Volkow. N. D. Neurocircuitry of Addiction, Neuropsychopharmacology reviews 35 (2010)

38. 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

39. Daily Sessions of Self-Administration
Reinstatement of Drug (Alcohol) Seeking with Drug-Associated Contextual Stimuli
Reinstatement
Daily Sessions of Self-Administration
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EXT S- S+

40. From: Cornish JL and Kalivas PW, J Addict Dis, 2001, 20:43-54.
Role of Glutamate and Dopamine Neurotransmission in Relapse to Drug-Seeking Behavior
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From: Cornish JL and Kalivas PW, J Addict Dis, 2001, 20:43-54.

41. 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

42. 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, 168:3-20.

43. Non-dependent Dependent
Positive
Reinforcement
Negative
Non-dependent
Dependent
Negative
Reinforcement
Positive
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44. Stress and Anti-stress Neurotransmitters Implicated in the Motivational Effects of Drugs of Abuse
Corticotropin-releasing factor 
Neuropeptide Y
Norepinephrine
Nociceptin (orphanin FQ)
Vasopressin
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Orexin (hypocretin)
Dynoprhin
Substance P

45. Brain Arousal-Stress System Modulation in the Extended Amygdala
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From: Koob, G.F Neuron 59:11-34

46. Regulation of the Mesolimbic Dopamine Circuit and Hypothalamus by the Extended Amygdala
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47. Compulsivity – Loss of Control Neuroplasticity with Increasing Use
Neuroplasticity in Brain Circuits associated with the Development of Addiction
Extended
Amygdala
Compulsivity – Loss of Control
Prefrontal
Cortex
Dorsal
Striatum
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Text in PPT
Nucleus
Accumbens
Mesolimbic DA
Neuroplasticity with Increasing Use
From: Koob and Volkow, Neurocircuitry of addiction, Neuropsychopharmacology Reviews, in press 47

48. Allostatic Change in Emotional State associated with Transition to Drug Addiction
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Adapted from: Koob GF and Le Moal M, Neuropsychopharmacology, 2001, 24:

49. 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

50. Neurobiology of Drug Addiction Koob 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)
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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