The Neurobiology of Alcoholism: Insights from the Dark Side of ...

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  • The Neurobiology of Alcoholism: Insights from the Dark Side of ...

    1. 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) 217-238
    2. 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. 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. 4. Progression of Drug Dependence From:Heilig M and Koob GF, Trends Neurosci, 2007, 30:399-406.
    5. 5. From: Koob GF, Alcohol Clin Exp Res, 2003, 27:232-243.
    6. 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. 7. Stages of the Addiction Cycle
    8. 8. Neurobiology of Addiction Koob, G. F. and Volkow. N. D. Neurocircuitry of Addiction, Neuropsychopharmacology reviews 35 (2010) 217-238
    9. 9. Binge/Intoxication Stage Koob, G. F. and Volkow. N. D. Neurocircuitry of Addiction, Neuropsychopharmacology reviews 35 (2010) 217-238
    10. 10. 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.
    11. 11. 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, 12:781-787.
    12. 12. Converging Acute Actions of Drugs of Abuse on the Ventral Tegmental Area and Nucleus Accumbens From: Nestler EJ, Nat Neurosci, 2005, 8:1445-1449.
    13. 13. Withdrawal/Negative Affect Stage Koob, G. F. and Volkow. N. D. Neurocircuitry of Addiction, Neuropsychopharmacology reviews 35 (2010) 217-238
    14. 14. Affective Dynamics Produced by Drug Administration in Non Dependent versus Dependent Subjects From: Solomon RL, American Psychologist, 1980, 35:691-712.
    15. 15. 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 Effects Negative Hedonic Effects of Withdrawal
    16. 16. Protocol for Drug Escalation All Rats (n=24): 2-hr SA session Fixed Ratio 1 0.25 mg cocaine/injection 1) Initial Training Phase Short Access (n=12) 22 x 1-hr SA session 2) Escalation Phase Long Access (n=12) 22 x 6-hr SA session Cocaine doses (µg): 0, 15.6, 31.2, 62.5, 125, 250 3) Dose-Effect Study Protocol from: Ahmed SH and Koob, Science, 1998, 282:298-300.
    17. 17. 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, 5:625-627.
    18. 18. Effect of α-flupenthixol on Cocaine Self-Administration in Escalated and Non-Escalated Animals From: Ahmed SH and Koob GF, unpublished results.
    19. 19. Decreased Dopamine D2 Receptor Activity in a Cocaine Abuser From: Volkow ND, Fowler JS, Wang GJ, Hitzemann R, Logan J, Schlyer DJ, Dewey S and Wolf AP, Synapse, 1993, 14:169-177.
    20. 20. Affective Dynamics Produced by Drug Administration in Non Dependent versus Dependent Subjects From: Solomon RL, American Psychologist, 1980, 35:691-712.
    21. 21. Anti-Reward Transmitters Implicated in the Motivational Effects of Drugs of Abuse Dynorphin … “dysphoria” CRF … stress Norepinephrine … stress
    22. 22. CNS Actions of Corticotropin-Releasing Factor (CRF)
    23. 23. Major CRF-Immunoreactive Cell Groups and Fiber Systems in the Rat Brain From: Swanson LW, Sawchenko PE, Rivier J and Vale W, Neuroendocrinology, 1983, 36:165-186.
    24. 24. 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
    25. 25. 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
    26. 26. Withdrawal-induced Increases in Extracellular Levels of CRF
    27. 27. Conditioned Place Aversion Produced by One Pairing of Naloxone in Morphine-Dependent Rats From: Gracy KN, Dankiewicz LA and Koob GF, Neuropsychopharmacology, 2001, 24:152-160.
    28. 28. CRF1 Specific Antagonists
    29. 29. Effects of Antalarmin on Place Aversion Induced by Naloxone-Precipitated Morphine Withdrawal From: Stinus L, Cador M, Zorrilla EP and Koob GF, Neuropsychopharmacology, 2005, 30:90-98.
    30. 30. Competitive CRF Antagonist Injected into the Amygdala Blocks Conditioned Place Aversion to Opiate Withdrawal From: Heinrichs SC, Menzagi F, Schulteis G, Koob GF and Stinus L, Behav
    31. 31. 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
    32. 32. 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.
    33. 33. Role of Corticotropin-releasing Factor in Dependence CRF antagonist effects on withdrawal- induced anxiety-like responsesDrug Cocaine Opioids Ethanol Nicotine ∆9 -tetrahydrocannabinol Withdrawal- induced changes in extracellular CRF in CeA ↑ ↑ ↑ ↑ ↑ CRF antagonist effects on dependence-induced increases in self- administration ↓ ↓ ↓ ↓ nt CRF antagonist reversal of stress-induced reinstatement ↓ ↓ ↓ ↓ nt ↓ ↓ ↓ ↓ ↓ * = aversive effects with place conditioning. nt = not tested. CeA = central nucleus of the amygdala. * From: Koob, G.F. 2008 Neuron 59:11-34
    34. 34. Preoccupation/Anticipation “Craving” Stage Koob, G. F. and Volkow. N. D. Neurocircuitry of Addiction, Neuropsychopharmacology reviews 35 (2010) 217-238
    35. 35. 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
    36. 36. Reinstatement Reinstatement of Drug (Alcohol) Seeking with Drug-Associated Contextual Stimuli SA EXT S- S+Daily Sessions of Self-Administration
    37. 37. Role of Glutamate and Dopamine Neurotransmission in Relapse to Drug-Seeking Behavior From: Cornish JL and Kalivas PW, J Addict Dis, 2001, 20:43-54.
    38. 38. 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
    39. 39. 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.
    40. 40. Positive Reinforcement Negative Reinforcement Non-dependentDependent Negative Reinforcement Positive Reinforcement
    41. 41. Stress and Anti-stress Neurotransmitters Implicated in the Motivational Effects of Drugs of Abuse Corticotropin-releasing factor↑ ↑ ↑ ↑ ↑ ↑ Norepinephrine Vasopressin Orexin (hypocretin) Dynoprhin ↓ ↓ Neuropeptide Y Nociceptin (orphanin FQ) Substance P
    42. 42. Brain Arousal-Stress System Modulation in the Extended Amygdala From: Koob, G.F. 2008 Neuron 59:11-34
    43. 43. Regulation of the Mesolimbic Dopamine Circuit and Hypothalamus by the Extended Amygdala
    44. 44. Neuroplasticity in Brain Circuits associated with the Development of Addiction From: Koob and Volkow, Neurocircuitry of addiction, Neuropsychopharmacology Reviews, in press Neuroplasticity with Increasing Use Compulsivity–LossofControl Mesolimbic DA Nucleus Accumbens Dorsal Striatum Prefrontal Cortex Extended Amygdala
    45. 45. Allostatic Change in Emotional State associated with Transition to Drug Addiction Adapted from: Koob GF and Le Moal M, Neuropsychopharmacology, 2001, 24:97-129.
    46. 46. 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
    47. 47. Neurobiology of Drug Addiction Koob Laboratory 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 Special thanks to: Mike Arends (Senior Research Assistant) 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 Scientist Heather Richardson Olivier George 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 Visiting Professors Choon-Gon Jang Charles Heyser

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