Novelty, Dopamine and Response to Amphetamine

There has been considerable emphasis on research aimed at determining the genetic factors responsible for phenotypic expression of increased drug abuse vulnerability. Identification of the multiple genetic factors that determine vulnerability is critically important and currently feasible with modern molecular technology. However, significant efforts also need to be directed at understanding the impact of intervening environmental factors that modify the trajectory of an individual's genetic vulnerability. In this competitive renewal application, we will investigate the effects of environmental enrichment during development on drug abuse vulnerability during adulthood. Evidence to date indicates that repeated exposure to novel stimuli (i.e., the "enriched" condition; EC) during the periadolescent period produces profound changes in response to novelty and response to drugs of abuse later in life. We have found that EC rats display less motivation for sucrose and for visual novelty, as well as less impulsivity for obtaining sucrose reward, compared to rats raised in an "impoverished" condition (IC). EC rats also show a reduction in amphetamine self-administration compared to IC rats when tested with low unit doses. These enrichment-induced behavioral changes are accompanied by a reduction in uptake and metabolism of dopamine (DA) in presynaptic terminals in medial prefrontal cortex (mPFC), a brain region known to be involved in both drug reward and behavioral inhibition, perhaps via a modulatory influence on DA activity in the nucleus accumbens (MAcc) and other related components of the motivational circuitry. The overall working hypothesis of this application is that exposure to novel environmental stimulation during development protects against stimulant abuse because there is a decrease in the incentive value of positive reinforcers and a concomitant increase in behavioral inhibition, with each of these processes being associated with changes in corticolimbic activity. The specific aims are to determine if environmental enrichment: 1. protects against escalating stimulant intake across long access sessions; 2. alters behavioral inhibition following stimulant exposure; 3. alters patterns of neuronal activity in corticolimbic and striatal regions involved in reward and inhibition; and 4. alters monoamine transporter function in corticolimbic and striatal regions involved in reward and inhibition.