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

Effects of amphetamine exposure during adolescence on behavior and prelimbic cortex neuron activity in adulthood

Repeated exposure to psychostimulants during adolescence produces long-lasting changes in behavior that may be mediated by disrupted development of the mesocorticolimbic dopamine system. Here, we tested this hypothesis by assessing the effects of amphetamine (AMPH) and dopamine receptor-selective drugs on behavior and neuron activity in the prelimbic region of the medial prefrontal cortex (PFC). Adolescent male, Sprague-Dawley rats were given saline or 3 mg/kg AMPH between postnatal day (P) 27 and P45. In Experiment 1, locomotor behavior was assessed during adulthood following challenges with a dopamine D1 (SKF 82958) or D2 (quinpirole) receptor-selective agonist. In Experiment 2, pre-exposed rats were challenged during adulthood with AMPH and a D1 (SKF 83566) or D2 (eticlopride) receptor-selective antagonist. In Experiment 3, the activity of putative pyramidal cells in the prelimbic cortex was recorded as rats behaved in an open-field arena before and after challenge injections with AMPH and one of the antagonists. We found that compared to controls, adolescent pre-exposed rats were more sensitive to the stimulant effects of AMPH and the dopamine receptor agonists, as well as to the ability of the antagonists to reverse AMPH-induced stereotypy. Prelimbic neurons from AMPH pre-exposed rats were also more likely to respond to an AMPH challenge in adulthood, primarily by reducing their activity, and the antagonists reversed these effects. Our results suggest that exposure to AMPH during adolescence leads to enduring adaptations in the mesocorticolimbic dopamine system that likely mediate heightened response to the drug during adulthood