Addiction Following Prenatal Cocaine Exposure

描述(由申请人提供)： 作为之前NIDA资助的K赠款(K02DA00354)的一部分，我的研究小组开发了一个在瑞士Webster(SW)小鼠身上的动物模型，以探索妊娠可卡因暴露的长期结构和功能后果的潜在机制。利用这个模型，我们可以分离出可卡因在促进临床相关的行为结果改变方面的独立作用，包括暴露在暴露的后代中随后成瘾的可能性。具体地说，我的实验室最近将注意力集中在研究可卡因对子宫内暴露的成年动物的增强效果上。我们利用一些行为范式进行了这些研究，包括可卡因自我给药、脑刺激奖励和可卡因诱导的运动敏化。我们所有三种方法的初步发现表明，产前暴露于可卡因的小鼠在成年后对可卡因的反应增强。由于这些发现的临床意义非常重要，我们建议在机械水平上进一步开展可卡因诱导的运动敏化的研究。 目前对NIDA独立科学家奖(K02)的竞争性续签要求是利用我们开发的可卡因诱导的运动敏化范式来确定可能支持在子宫内暴露于可卡因的成年动物对可卡因的增强行为反应的分子机制。我们发现，与对照组相比，暴露在可卡因中的小鼠在产前表现出明显的运动敏感化减弱，当最后一次注射可卡因21天后受到挑战时，刻板行为显著增强。这项K02申请中提出的研究的目标是确认和扩展这些行为发现，并确定这种现象的分子基础的各个方面。通过在孕期可卡因暴露的产前模型中进行这样的实验，我们的目标是将大脑中分子变化的特定模式关联起来，这些模式有助于在比较来自不同产前处理组的动物时观察到行为敏感化的差异。这些信息将提供关于产前暴露于可卡因的小鼠对可卡因的易感性增强的独特的机械性见解，这可能导致改善对暴露于可卡因的后代的成瘾预防。

DESCRIPTION (provided by applicant): 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.