Early Drug Exposure and Drug Reward Mechanisms

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DESCRIPTION (provided by applicant): Attention-deficit/hyperactivity disorder (ADHD) affects attention and motor capacities in approximately 6% of school-aged children, making it the most prevalent childhood disorder. ADHD can be treated effectively with stimulants including methylphenidate (MPH; RitalinTM), which are indirect dopamine (DA) agonists, and their use is rising. However, the use of such stimulants has been limited by concerns over their abuse or the possible role they play as a "gateway" to the abuse of other substances. Recent clinical data show that ADHD children treated with stimulants experience an 85% reduction in substance abuse compared with those who do not receive pharmacotherapy. The interpretation of these clinical observations, however, is difficult since effectively treated ADHD patients have improved psychosocial and academic skills that reduce other risk factors, such as social impairment. In addition, they do not address potential mechanisms leading to alternative interpretations including the possibility that early treatment with MPH can imprint on the underlying neurobiological substrate of stimulant abuse. In other words, juvenile exposure to MPH potentially can produce enduring effects on the neurobiology of the developing brain that outlast the period of drug treatment itself. Some of these questions can potentially be answered using animal models and it has been shown that chronic exposure to stimulant drugs, such as MPH, causes long-lasting increases in rewarding effects, thereby increasing vulnerability to substance abuse. However, these studies have been performed in adult animals limiting their interpretation for drug treatment in juvenile (developing) brains. We have, therefore, developed an animal model using MPH exposure in juvenile rats. In this model, MPH exposure made moderate doses of cocaine aversive and high doses less rewarding later in life demonstrating reduced vulnerability to stimulant abuse. Thus, our results indicate that imprinting and/or age differences in pharmacokinetics of MPH could mediate its enduring effects. In the proposed set of studies we endeavor to determine: 1) the age-related contribution of bioavailability of MPH to cocaine reward later in life; 2) the effect of chronic MPH treatment on dopamine release in the pre-pubertal rat; 3) whether pre-pubertal exposure to MPH changes dopamine receptor expression; and 4) the role of dopamine in the underlying mechanism of MPH-induced changes in the pre-pubertal rat.