Drug abuse is a significant social and medical problem that directly involved over two million people in the U.S. The goal of neurobiological research is to understand the complex mechanisms underlying euphoria, drug-seeking behavior and craving so that treatment strategies can be identified to combat drug abuse. The ability of psychomotor stimulant drugs to enhance the salience and significance of reward-related stimuli may be a potent determinant of the behavioral effect of these drugs. In addition to these incentive motivational effects, stimulant drugs also produce behavioral sensitization that results in augmentation of behavior after repeated drug exposures. the ventral striatum (nucleus accumbens) has been implicated in both responding for reward-related stimuli, sensitization, and the reinforcing properties of stimulants (cocaine and amphetamine). The nucleus accumbens is a region of the forebrain that has been suggested to be a limbic-motor interface that gates or mediates motivational response output. Our previous research was the first to demonstrate that dopaminergic neurotransmission within the nucleus accumbens was a component of the neural circuitry involved in incentive motivation. The current proposal seeks to examine the role of dopamine (DA) receptor subtypes within the nucleus accumbens in enhanced responding for reward-related stimuli in sensitized rats. Direct microinfusions of neurotransmitters or drugs will be used to accomplish these goals using behavioral measures of motor activity and responding for reward-related stimuli (termed """"""""conditioned reinforcement""""""""). There are two major objectives of these studies: 1) To investigate the ability of cocaine and amphetamine sensitization to affect responding for conditioned reinforcement and enhanced responding after drug administration. 2) To examine the ability of intra-accumbens infusions of selective dopaminergic (D1) receptor agonists (SKF82958, SKF81297) to enhance responding for conditioned reinforcement, and determine whether selective DAantagonists can block these effects in cocaine sensitized subjects. The ventral striatum is hypothesized to be critical for reward-related processes involved in both conditioned reinforcement and in sensitization. The studies should (1) contribute to our understanding of the role of the ventral striatum in the effects of psychomotor stimulant drugs and (2) help establish the relevance of the conditioned reinforcement model to processes that may contribute to drug dependence and craving.
