1. Addiction: Transition from Molecular to Behavioral Understanding John Neumaier, M.D., Ph.D. Department of Psychiatry Harborview Medical Center and University of Washington

2. Goals –How does a psychiatrist think about addiction? –Review some psychological and learning aspects of addiction theories –Review some molecular events associated with addiction –Consider the substrates of enduring addiction and risk for relapse

4. Impaired Response Inhibition and Salience Attribution Goldstein and Volkow (2002) Am J Psychiatry 159:1642

5. Bolla et al. (2004) J Neuropsychiatry Clin Neurosci 16:456. Rostral Anterior Cingulate Cortex activation in Stroop task (tests executive function)

7. What are the psychological aspects of addiction? –Emotional (liking) –Motivational (wanting) –Learning (cognitive and associative) Robinson and Berridge (2003) Annu Rev Psychol 54:25-53.

9. Wanting Motivation to obtain a reward (such as a drug) –Can be independent of “liking” the reward Pathological wanting = craving The importance of the reward grows with repeated exposure (sensitization) Can be inferred by how hard someone will work to obtain the reward

11. Sensory, insular ctx inputs S/R associations Sensorimotor? dorsolateraldorsomedial PFC inputs S/R associations Limbic? Learning

12. Molecular adaptations associated with addiction are likely to be stage specific –Sensitization –Tolerance –Escalation –Withdrawal –Extinction –Relapse

13. tolerance sensitization

18. What are the neural plasticity events associated with these adaptations?

19. “Incubation” of craving Yavin Shaham

20. What are the effects of social stress on drug self administration?

22. Stress Induced Reinstatement Shalev et al (2002) Pharmacol Rev 54:1-42.

23. Escalation

24. What might pharmacological treatments for addiction look like? Prevent initial drug events? Shift balance of + and - features? Prevent reinstatement? Facilitate extinction learning? Deconstruct reconsolidation of memory? Shift from out of control to regulated use?

25. Serotonin and Reward Many different receptors implicated 5-HT 1B and 5-HT 6 have roughly opposing effects

26. Andrews and Lucki Psychopharm. (2001) 155:221–229

28. Neumaier et al (2002) J Neurosci 22:10856.

29. 0.5 1 1.5 2 2.5 3 3.5 4 1BGFP UNH EtOH consumed (g/kg) * Hoplight et al (2006) Alcohol 38:73.

30. 5-HT 1B & “Binge Cocaine” 3 weeks of noncontingent cocaine injections –15 mg/kg ip every hour X 3 injections daily or 1 day of 3 cocaine injections Saline controls Unhandled cage controls 5-HT 1B mRNA by ISHH

31. Hoplight et al (2006) Neuropharmacol

33. Study Design Guide cannula Food restriction Behavioral testingGene transfer sacrifice

34. Mitchell et al (2007) Neuropsychopharm EPub

35. Operant Conditioning 1st session –10 sucrose pellets presented noncontingently –50 trials of stimulus cue light with lever presentation, response within 10 sec rewarded with sucrose pellet 2nd and 3rd session, same except 3 noncontingent sucrose pellets

36. Mitchell et al (2007) Neuropsychopharm EPub

37. Is learning deficit due to increased 5-HT 6 activity? SB258585 or BGC20- 761 given immediately after 2 nd day session had no effect SB258585 (5 mg/kg ip) or saline vehicle immediately before 1 st and 2 nd sessions

38. Is effect of 5-HT 6 receptor overexpression subregion specific? Voorn et al TINS (2004) 27:468

39. 5-HT 6 overexpression in NAcc shell No significant effects on locomotor sensitization Conditioned place preference, compared HA6/GFP to GFP injected animals

40. Conditioned place preference to cocaine (20 mg/kg) Time (Sec) GFP HA6 Paired Side CocSalNeut Paired Side CocSalNeut

41. * 5-HT 6 antagonist & cocaine reward Ro4368554 or vehicle given before subthreshold doses of cocaine (5 mg/kg) Ferguson et al 2007 Biol Psych in press.

42. Implications Impaired… or stable? Dopamine and Serotonin - opposing factors? 5-HT 6 receptors and ACh striatum GABA ACh DA 5-HT 5-HT 6 Glu