BEHAVIORAL CONSEQUENCES OF PRENATAL EXPOSURE TO COCAINE

这是一项研究长期行为后果的建议 胎儿接触可卡因。提出了四个相互关联的子项目 在目标L到4。项目L和2发现结构异常在 成年兔产前暴露于扣带回皮质的实验研究 可卡因。联想学习，对有害刺激的反应和 注意过程依赖于扣带回的正常功能 成年可卡因患者的大脑皮层和上述三种功能均受损。 后代。Aim L现在将确定儿童是否存在认知缺陷 可卡因后代是由于训练依赖的异常改变 扣带回皮质及相关结构的神经活动。 多巴胺(DA)D1受体介导的信号转导受损 前扣带状和纹状体内(项目5)。D1R已经被 牵涉到注意力过程中。因此，目标2(与 目标4)将确定这些认知缺陷是否与 可卡因子代与对照组在训练诱导中的差异 扣带回皮质内DA的释放及DA激动剂是否可能 改善认知缺陷。目标3表明，赤字 在d1联结中(项目5)与d- 苯丙胺诱导的运动反应依赖于脑内的d1信号。 纹状体。拟议研究(目标3)将：使用多巴胺激动剂和拮抗剂 准确定义由以下因素造成的运动功能障碍 产前接触可卡因，评估可卡因后代的易感性 对慢性可卡因的行为敏感化，以及测试药物疗法 修复D_1/G蛋白偶联或绕过信号缺陷 转导，以使运动功能正常化。AIM 4将使用 体内微透析与体外配体结合分析 目标3中药物行为效应的神经化学机制。 这些实验将把可卡因后代的行为异常联系起来 在特定的大脑区域有异常的功能，并可能提供 恢复大脑功能的治疗方法。

This is a proposal to examine the long-term behavioral consequences of fetal exposure to cocaine. Four interrelated subprojects are proposed in Aims l to 4. Projects l and 2 found structural abnormalities in the cingulate cortex of adult rabbits that had been exposed prenatally to cocaine. Associative learning, reaction to noxious stimuli and attentional processes depend on the normal functioning of the cingulate cortex and all three of these functions were impaired in adult cocaine progeny. Aim l will now determine whether the cognitive deficits in cocaine progeny are due to abnormal training-dependent alterations in the neural activity of the cingulate cortex and related structures. Dopamine (DA) D1 receptor-mediated signal transduction is impaired in anterior cingulate and in striatum (Project 5). The D1 receptor has been implicated in attentional processes. Thus, Aim 2 (in conjunction with Aim 4) will determine whether these cognitive deficits are related to differences between cocaine progeny and controls in the training-induced release of DA within cingulate cortex and whether DA agonists might ameliorate the cognitive deficits. Aim 3 demonstrated that the deficits in D1 coupling (Project 5) are associated with deficits in d- amphetamine-induced motor responses that rely upon D1-signalling in the striatum. Proposed studies (Aim 3) will: use DA agonists and antagonists to define precisely the impairments in motor function produced by prenatal cocaine exposure, assess the vulnerability of cocaine progeny to behavioral sensitization by chronic cocaine, and test drug therapies to repair D1/G protein coupling or by-pass the deficit in signal transduction in order to normalize motor function. Aim 4 will use microdialysis in vivo and ligand binding in vitro to analyze neurochemical mechanisms for the behavioral effects of drugs in Aim 3. These experiments will link behavioral abnormalities in cocaine progeny with abnormal functioning in specific brain regions and may offer therapeutic approaches for restoring brain function.