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Study of addiction in animal models

Study of addiction in animal models. Bill Carlezon , Ph.D Behavioral Genetics Laboratory Department of Psychiatry Harvard Medical School McLean Hospital. Addiction…. is a reward deficit disorder is a stimulus-response perseveration (habit) disorder is a stress-excess disorder

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Study of addiction in animal models

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  1. Study of addiction in animal models Bill Carlezon, Ph.D Behavioral Genetics Laboratory Department of Psychiatry Harvard Medical School McLean Hospital

  2. Addiction… • is a reward deficit disorder • is a stimulus-response perseveration (habit) disorder • is a stress-excess disorder • involves neuroadaptations that occur in stages/phases

  3. Reward deficit and the need for more From: Solomon RL, American Psychologist, 1980, 35:691-712.

  4. The need for more

  5. Will work harder

  6. Stages of addiction (older formulation) Courtesy of George Koob

  7. Stages of addiction (newer formulation) 3 2 1 Koob, G. F. and Volkow. N. D. Neurocircuitry of Addiction, Neuropsychopharmacology reviews 35 (2010) 217-238

  8. Drug-induced neuroadaptations Social Recurrent Dorsal Striatum Relapse Koob, G. F. and Volkow. N. D. Neurocircuitry of Addiction, Neuropsychopharmacology reviews 35 (2010) 217-238 Kalivas, P .W., O’Brien, C., Neuroplasticity and addiction, Neuropsychopharmacology reviews 33 (2008) 160-180

  9. Example from Carlezon lab Drugs/ Stress to PFC to AMG Based on Nestler and Carlezon, 2006

  10. Interactions of cues and habits 3 2 1 Koob, G. F. and Volkow. N. D. Neurocircuitry of Addiction, Neuropsychopharmacology reviews 35 (2010) 217-238

  11. Measurement of cue-induced craving and withdrawal in addicts in laboratory settings • Self-reported craving and withdrawal • Galvanic skin response (GSR) • Increased heart rate • Increased respiration rate • Salivation • Runny nose • Watery eyes, blinking

  12. I felt angry or frustrated, either with myself or because things were not going my way. Emotional states I was in a good mood and felt like getting high. Impulsive choices I wanted to see what would happen if I tried just one hit. Social pressure Someone offered me a hit. I saw others using. Drug cues When I saw “works” or heroin I just had to give in. Self-reported reasons for relapse in opiate addicts Heather N et al. (1991) Addict Behav 16: 41-49

  13. (2002) Addiction 97: 155-167

  14. extinction Conditioned response is extinguished

  15. craving withdrawal Childress AR et al. (1986) Br J Addiction 81: 655-660

  16. “Efforts to improve cue-exposure’s effectiveness must be guided by findings from ongoing studies in animal extinction… Indeed, it is rare to find any area of clinical endeavor that can take such immediate clinical advantage of basic findings from the animal laboratory.” Conklin and Tiffany (2002)

  17. Lever Press/Cue Training Lever Press Extinction Test Session(s) (Cue Extinction) Rate of Lever Pressing Rate of Lever Pressing Rate of Lever Pressing Time Time Time

  18. 100 0 Naloxone -100 Morphine-dependent -200 Change Scores -300 -400 -500 -600 -700 ** -800 Conditioned place aversion Myers and Carlezon, 2010

  19. Naloxone Morphine-dependent ?

  20. 400 200 0 -200 -400 -600 -800 -1000 -1200 ? Naloxone Change Scores * ** ** Test 1 Test 2 Test 3 Test 4 Myers and Carlezon, 2010

  21. 400 200 0 -200 -400 -600 -800 -1000 -1200 Change Scores * ** ** Test 1 Test 2 Test 3 Test 4 0 -200 -400 Change Scores -600 (no intervening exposures) -800 -1000 Myers and Carlezon, 2010

  22. ? Naloxone Morphine-dependent + saline + DCS

  23. Saline DCS 100 0 * -100 -200 -300 -400 -500 -600 -700 -800 -900 ? Naloxone + saline or DCS Change Scores Test 1 Test 2 Myers and Carlezon, 2010

  24. Skin conductance Self-reported craving

  25. Addiction… • is a reward deficit disorder • is a stimulus-response perseveration (habit) disorder • is a stress-excess disorder • involves neuroadaptations that occur in stages/phases and 5. may have dimensions that are reversible with behavior-based approaches 6. is persistent and could be perpetuated by poorly implemented therapies

  26. McLean Labs Bruce Cohen Cecile Beguin Funding NIMH, NIDA, DOD, NARSAD, HHMI Acknowledgements RTI Ivy Carroll Temple Lee-Yuan Liu-Chen UNC Bryan Roth Carlezon Lab (1998-present) Andrea Pliakas, Andreas Arvanitogiannis, Rebecca Ralph, Sonia Guediche, Steve Mague, Brian Gilliss, Elena Chartoff, HilarieTomasiewicz, Mark Todtenkopf, Edward Meloni, Ali Jackson, Jackie Marcus, Maria Papadopoulou, Jennifer DiNieri, Katie Famous, Drew Smith, Jessica Pohlman, Aram Parsegian, Lyle Gerety, Tracie Paine, Dost Ongur, Allison Knoll, Matt Barhight, Toni Dow, Tiffany Lin, Hannah Kang, Christina Nemeth, Katy Reedy, Anita Bechtholt, Peter Campbell, Melissa Chen, Allison Sawyer, John Muschamp, Ashlee Van’t Veer, David Potter, Kristen Lee, Karyn Myers, Miranda Gallo, Tredick Goodman

  27. Key Definitions Addiction — a chronically relapsing disorder that is characterized by a compulsion to seek and consume drug (or other stimulus), loss of control in limiting intake, and emergence of a negative emotional state (e.g. dysphoria, anxiety, irritability) when access to the drug or stimulus is prevented. Compulsivity — perseveration of responding in the face of adverse consequences or incorrect responses in choice situations. Compulsive disorders — characterized by anxiety and stress before committing a compulsive repetitive behavior, and relief from the stress by performing the compulsive behavior (DSM IV American Psychiatric Association). Compulsive drug seeking — a maladaptive Stimulus–Response habit in which the ultimate goal of the behavior has been devalued, perhaps through tolerance to the rewarding effects of the drug (Everitt BJ, Belin D, Economidou D, Pelloux Y, Dalley JW, Robbins TW. Philos Trans R SocLond B BiolSci 2008, 363:3125-3135.)

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