Developmental consequences of in utero cocaine

描述(由申请人提供)： 在兔发育的关键时期，产前暴露可卡因选择性地改变特定类型神经元的结构以及大脑皮层富含多巴胺(DA)的区域(如前额叶和前扣带回皮质)中D1多巴胺(DA)受体的偶联。与这个模型系统中的发现一致，在宫内暴露于可卡因的儿童表现出类似注意力缺陷障碍的发育表型。在宫内可卡因暴露的兔模型中，将研究D1受体的特定表达模式、DA调节的皮质中间神经元的神经生理特性的变化以及注意力中断的情况。药物操作将确定在利用注意力系统的任务中表现不佳的D1受体功能障碍的直接作用。初步数据表明，在子宫内，可卡因会导致系统在基线状态下正常工作，但当系统受到挑战时，行为异常就会出现。在这一动物模型中详细描述产前暴露于可卡因的发育后果将有助于理解扰乱临床人群行为的潜在分子和细胞机制。

DESCRIPTION (provided by applicant): Prenatal cocaine exposure during critical periods of development in rabbits selectively alters the structure of specific types of neurons and the coupling of the D1 dopamine (DA) receptor in DA-rich regions of the cerebral cortex, such as prefrontal and anterior cingulate cortices. Consistent with findings in this model system, children exposed to cocaine in utero exhibit a developmental phenotype that resembles attention deficit disorder. The specific expression patterns of the D1 receptor, changes in neurophysiological properties of cortical interneurons modulated by DA, and disrupted attention will be investigated in the rabbit model of in utero cocaine exposure. Pharmacological manipulations will establish a direct role of D1 receptor dysfunction in the poor performance on tasks that tap attention systems. Preliminary data suggest that in utero cocaine results in systems that function normally at baseline, but when the system is challenged, behavioral abnormalities emerge. Detailed characterization of the developmental consequences of prenatal cocaine exposure in this animal model will facilitate an understanding of the underlying molecular and cellular mechanisms that disrupt behavior in the clinical population.