The effects of repeated amphetamine exposure during adolescence on behavior and prefrontal cortex function

Cognitive impairment and altered drug sensitivity are two commonly reported behavioral outcomes of amphetamine abuse. Individuals who begin using amphetamine during adolescence may have an increased risk of developing drug-related problems because of maturational changes in mesocorticolimbic circuitry that are specific to this stage of development. The studies presented here were designed to assess long-term effects of amphetamine on cognition, dopamine receptor function, and prefrontal cortex (PFC) activity, with a focus on the consequences of drug exposure during adolescence. Chapter 1 includes a review of the literature on substance abuse and PFC dysfunction along with the specific aims of the studies described in the following chapters. Chapter 2 describes studies of drug-induced psychomotor activity and measures of working memory in rats exposed to amphetamine during adolescence or adulthood. Results suggest long-term effects of amphetamine on cognition vary according to the age of exposure. The experiments in Chapter 3 investigated the protracted effects of repeated amphetamine exposure during adolescence on psychomotor behavior and medial PFC function in young adulthood. Relative to controls, rats pre-exposed to amphetamine displayed psychomotor sensitization when challenged with amphetamine and heightened responsiveness to D1 and D2 receptor agonists. Expression of sensitization to amphetamine was attenuated in pre-exposed rats following challenges with a D1 or D2 receptor antagonist. The long-term functional impact of amphetamine on medial PFC neurons was assessed using single-unit recordings in awake behaving rats. Young adult rats were challenged with amphetamine followed by a D1 or D2 receptor antagonist. The proportion of amphetamine-responsive neurons and the pattern of spike activity was altered in animals exposed to amphetamine during adolescence relative to controls. Finally, Chapter 4 includes a general discussion on the results and implications of the experiments described in this dissertation. Taken together, the research presented here demonstrates age-dependent effects of amphetamine on cognition and highlights the long-lasting impact of amphetamine exposure on dopamine and medial PFC function