Novelty, Dopamine and Response to Amphetamine

Evidence indicates that repeated early life exposure to an enriched environment produces changes in response to novelty and response to drugs of abuse later in life. The overall working hypothesis of this proposal is that exposure to novel environmental stimulation during development decreases responding for nondrug and drug reinforcers during adulthood and that this behavioral change is due, at least in part, to enhanced basal OA activity in the mesocorticolimbic reward system. The specific aims of the proposed experiments are to determine if environmental enrichment alters: (1) extinction or reinstatement of amphetamine seeking behavior; (2) the ability of nondrug reinforcers to decrease amphetamine self-administration; (3) neuronal processing in the nucleus accumbens (Nacc) and medial prefrontal cortex (mPFC) in response to nondrug reinforcers; and (4) activity of the OA transporter (OAT) and vesicular monoamine transporter (VMAT2) in mPFC. In the proposed experiments, rats will be raised from 21 days of age in either an enriched condition (EC), social condition (SC) or imporverished condition (IC). At 50 days of age, rats from each condition will be trained to self-administer amphetamine at one of various doses. Extinction and reinstatement of responding for amphetamine will be examined, and the ability of a concurrent alternative nondrug reinforcer (sweet solution or visual novelty) to reduce amphetamine self-administration will be examined in EC, SC and IC rats. To identify the critical neural mechanisms that underlie these enrichment-induced behavioral changes, separate groups of EC and IC rats will be examined for single-unit neuronal activity in the mPFC, Nacc core and Nacc shell while having access to sweet solution or novelty. Other experiments will use in vivo voltammetry or in vitro binding/uptake to access potential changes in OAT or VMAT2 in EC and IC rats. To the extent that both novelty and drugs of abuse activate the same mesocorticolimbic OA circuitry, this would suggest that novel stimulation may substitute for drug reward. Novelty-induced reductions in amphetamine self-administration would provide the impetus for examining the effectiveness of presenting enriching stimulation in drug abuse prevention interventions in humans prone to abuse drugs. The long-term objective of our work is to design biologically-relevant, behavioral treatment and prevention strategies that can be evaluated in a controlled human study.