NOVELTY, DOPAMINE AND RESPONSE TO AMPHETAMINE

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Our overall working hypothesis is that exposure to novel stimuli activates the mesolimbic dopamine (DA) reward pathway in a manner similar to drugs of abuse. In support of this hypothesis, we now have clear neurochemical evidence that novelty activates the mesolimbic DA system in rats. At the behavioral level, we also found that rats raised from weaning in an environment enriched with novel stimuli show a reduction in intravenous amphetamine self-administration as adults compared to rats raised in isolation. However, it is not known if the reduction in amphetamine self-administration reflects an environment-induced alteration in mesolimbic DA activity, nor is it known if brief exposure to novelty during young adulthood will also reduce amphetamine self-administration. The present project will determine if environmental enrichment during development alters mesolimbic DA activity. In vivo voltammetry and electrophysiological recording techniques, as well as in vitro cellular techniques, will be used to answer this question. These neurochemical experiments will begin with the nucleus accumbens, although other brain regions (e.g., prefrontal cortex, extended amygdala, hippocampus) will be examined in later studies. At the behavioral level, environment-induced differences in amphetamine self-administration will be examined using both fixed ratio and progressive ratio schedules of reinforcement. Control experiments will determine if environment-induced differences observed with amphetamine self- administration generalize to sucrose reinforcement. Finally, we will examine if brief exposure to novelty during young adulthood also reduces amphetamine self-administration. Based on our working hypothesis, we predict that novelty will substitute for amphetamine reward. If novelty reduces amphetamine self-administration in rats, this preclinical information would provide the impetus for examining the effectiveness of presenting highly novel stimulation in drug abuse prevention and/or treatment interventions in humans. The long-term objective of this work is to design a biologically relevant prevention intervention strategy that can be evaluated in a controlled human study.