As part of a previously NIDA funded K grant (K02DA00354) my research group has developed an animal model in Swiss Webster (SW) mice to explore mechanisms underlying long-lasting structural and functional consequences of gestational cocaine exposure. Utilizing this model we can isolate the independent effect of cocaine in contributing to altered behavioral outcomes of clinical relevance, including the liability for subsequent addiction in exposed offspring. Specifically, my laboratory has recently focused attention on studying the reinforcing efficacy of cocaine in adult animals exposed to cocaine in utero. We have pursued these studies utilizing a number of behavioral paradigms including cocaine self-administration, brain stimulation reward, and cocaine-induced locomotor sensitization. Our preliminary findings from all 3 methods suggest that mice prenatally exposed to cocaine demonstrate an augmented response to cocaine when tested as adults. As the clinical implications of these findings are profoundly important, we are proposing to further pursue our studies of cocaine-induced locomotor sensitization at a mechanistic level. The current request for a competing renewal of a NIDA Independent Scientist Award (K02) is to utilize the cocaine-induced locomotor sensitization paradigm that we have developed to identify molecular mechanisms that may underlie the augmented behavioral response to cocaine evident in adult animals exposed to cocaine in utero. We have discovered that when compared to controls, mice exposed to cocaine prenatally demonstrate a significant blunting of locomotor sensitization, and a significant augmentation of stereotypic behaviors when challenged 21 days after their last cocaine injection The goal of the research proposed in this K02 application is to confirm and extend these behavioral findings, and to identify aspects of the molecular basis of this phenomenon. By performing such experiments in a prenatal model of gestational cocaine exposure our goal will be to correlate specific patterns of molecular changes in the brain that contribute to differences in behavioral sensitization observed when comparing animals from different prenatal treatment groups. Such information will provide unique mechanistic insights regarding an enhanced vulnerability of prenatally cocaine-exposed mice to cocaine, which may lead to improved prevention of addiction in cocaine-exposed offspring.
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