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分项目 目标1至4。项目l和项目2发现， 成年家兔的扣带回皮质， 可卡因联想学习，对伤害性刺激的反应， 注意力过程依赖于扣带回的正常功能 皮质和所有这三种功能在成年可卡因中受损 后代我现在要确定的是， 可卡因后代是由于异常的训练依赖性改变， 扣带皮层和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， 前扣带回和纹状体（项目5）。D1受体已经被 与注意力过程有关因此，目标2（与 目标4）将确定这些认知缺陷是否与 可卡因子代和对照组在训练诱导的 扣带回皮质内DA的释放以及DA激动剂是否可能 改善认知缺陷。目标3表明， D1偶联（项目5）与d- 安非他明诱导的运动反应，依赖于D1-信号在 纹状体拟定的研究（目标3）将：使用DA激动剂和拮抗剂 精确定义运动功能的损伤， 产前可卡因暴露，评估可卡因后代的脆弱性 慢性可卡因引起的行为敏感化， 修复D1/G蛋白偶联或绕过信号缺陷 转导，以使运动功能正常化。目标4将使用 体内微透析和体外配体结合分析 目的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 大脑特定区域功能异常， 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.