The challenge in recovering from addiction and maintaining abstinence is two-fold. First, a recovering addict must inhibit drug-seeking behaviors and achieve abstinence. Second, the addict must establish a new, non-drug reinforced behavioral repertoire that is rewarding and satisfying. Although research is establishing the importance of explicit extinction training in reducing vulnerability to reinstatement of drug-seeking and relapse, little attention has been given to the role of non-drug reinforcers in the extinction process. Using conditioned place preference as a measure of the incentive value of contextual cues in eliciting approach behavior, this project systematically examines the role of new, non-drug reinforcement learning in facilitating the extinction of previously, drug- reinforced approach behavior and evaluates the impact of non-drug facilitated extinction on subsequent vulnerability to reinstatement. The role of dopamine in addiction is well documented if not entirely understood. It is believed to play a role both in the acquisition of drug reinforced behavior as well as its expression. This project investigates a novel hypothesis that tonic dopamine mediates the compulsive expression of previously learned, drug-reinforced behaviors while phasic dopamine activity mediates the modulation of previous learning as well as the acquisition of new learning, including non-drug reinforcement. Consequently, a potential therapeutic strategy would be the differential manipulation of tonic and phasic dopamine. Using transgenic mouse lines in which tonic and phasic dopamine activities are altered independent of each other, the differential contribution of tonic and phasic dopamine to the extinction of drug-reinforced behavior and the acquisition of alternative, non-drug behaviors will be investigated. Finally, nicotinic receptors have been shown to differentially modulate tonic and phasic dopamine release, providing a potential pharmacological strategy to pursue the above hypothesis. This project will examine the effects of currently available nicotinic acting drugs on the extinction of drug-reinforced behaviors and the acquisition of alternative, non-drug rewarded behaviors. As the role of nicotinic receptors in modulating dopamine is not fully understood, the project will use slice physiology to further characterize nicotinic modulation of dopamine in order to identify more specific targets for future drug development. PUBLIC HEALTH RELEVANCE: The primary goal of this project is to characterize the role of non-drug reward in the extinction of established, drug-reinforced behavior focusing on dopaminergic substrates that may critically mediate this relationship. A specific pharmacological strategy to enhance new learning and facilitate extinction of drug-seeking is proposed and developed. This work will contribute to the development of better behavioral approaches to addiction treatment, further elucidate the neural substrates underlying the shift from drug- to non-drug reinforcement critical in sustained recovery and provide preclinical evidence for a specific pharmacological target.

R01DA025875

2008-09-19

2013-05-31