Presentation on theme: "Addiction: Transition from Molecular to Behavioral Understanding John Neumaier, M.D., Ph.D. Department of Psychiatry Harborview Medical Center and University."— Presentation transcript:
Addiction: Transition from Molecular to Behavioral Understanding John Neumaier, M.D., Ph.D. Department of Psychiatry Harborview Medical Center and University of Washington
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
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
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?
Serotonin and Reward Many different receptors implicated 5-HT 1B and 5-HT 6 have roughly opposing effects
Andrews and Lucki Psychopharm. (2001) 155:221–229
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
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
Is effect of 5-HT 6 receptor overexpression subregion specific? Voorn et al TINS (2004) 27:468
5-HT 6 overexpression in NAcc shell No significant effects on locomotor sensitization Conditioned place preference, compared HA6/GFP to GFP injected animals
Conditioned place preference to cocaine (20 mg/kg) Time (Sec) GFP HA6 Paired Side CocSalNeut Paired Side CocSalNeut
* 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.
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