PRENATAL COCAINE ALTERS CORTICAL DOPAMINE FUNCTION

描述：(申请人摘要) 在过去的几年里，可卡因滥用的惊人增加 十年来，怀孕期间使用可卡因的情况普遍存在， 估计在一些地区高达8%到30%。因此，在那里 现在有相当数量的儿童接触到了 可卡因在发育初期的影响。可卡因 在怀孕期间使用似乎与各种不同的 子代的神经行为异常。虽然一些影响是由 胎儿接触可卡因在新生儿中出现暂时性，有 有迹象表明，可能会出现一些长期赤字。尤其是， 注意缺陷多动障碍(ADDH)的发病率似乎是 在出生前接触可卡因后显著增加。而这些 临床研究极易提示妊娠的有害影响 暴露在可卡因中，需要在实验室动物中进行对照研究 为了更全面地了解孕期使用可卡因的效果 对后代的影响，并找到扭转赤字的方法。这个 这一提议的总体假设，其强劲的初步数据是 提出的观点是，产前接触可卡因会扰乱 多巴胺输入到后代的前额叶皮质，这样的 缺陷反映在认知缺陷上，最明显的是 压力很大的环境。我们建议使用敏感度来继续这一假设。 用生物化学和行为学方法研究给药大鼠的子代 怀孕期间吸食可卡因。生化技术将包括体外和 突触前和突触后神经元活动的活体测量 前额叶皮质的多巴胺能终末。应激诱导的改变 在空间工作记忆的行为测量中，将通过 在延迟交替任务中的表现。压力将由以下因素引起 使大鼠暴露于引起焦虑的B-咔啉药物或 紧张的嗅觉提示。胎儿期接触铅引起的异常 可卡因将在出生后3岁接受检查。其效果将是 正如我们的初步数据显示的那样，在雄性和雌性后代中都有 孕期接触可卡因的一些性别特有的影响。当我们 预计这类研究将为 产前可卡因对前额叶皮质功能的影响 希望那些扭转赤字的研究 药理学上将产生积极的社会和经济影响 为药物的合理选择和新药物的开发提供指导 治疗产前暴露于可卡因的有害影响的药物。

DESCRIPTION: (Applicant's Abstract) The alarming increase in cocaine abuse that has occurred over the last decade has been reflected in the prevalence of cocaine use during pregnancy, estimated to be as high as 8% to 30% in some regions. Consequently, there is now a sizable population of children that have been exposed to the effects of cocaine during the initial stages of their development. Cocaine use during pregnancy appears to be associated with a variety of neurobehavioral abnormalities in the progeny. While some of the effects of fetal exposure to cocaine appear transiently in neonates, there are indications that some long-lasting deficits may occur. In particular, the incidence of attention deficit hyperactivity disorder (ADDH) appears to be markedly increased following prenatal exposure to cocaine. While these clinical studies are extremely suggestive of harmful effects of gestational exposure to cocaine, controlled studies in laboratory animals are needed in order to understand more fully the effect that cocaine use during pregnancy has on the offspring, and to find ways of reversing the deficit. The overall hypothesis of this proposal, for which strong preliminary data are presented, is that prenatal exposure to cocaine can disturb the function of the dopamine input to the prefrontal cortex of the progeny, and that such a deficit is reflected in cognitive deficits that are most apparent under stressful conditions. We propose to pursue this hypothesis using sensitive biochemical and behavioral measurements to study the offspring of rats given cocaine during pregnancy. Biochemical techniques will include in vitro and in vivo measures of neuronal activity pre- and postsynaptic to the dopaminergic terminals in the prefrontal cortex. Stress-induced alterations in behavioral measures of spatial working memory will be assessed by performance in a delayed alternation task. Stress will be induced by exposing rats to the effects of either an anxiogenic B-carboline drug or a stressful olfactory cue. Abnormalities induced by prenatal exposure to cocaine will be investigated at 3 postnatal ages. The effect will be pursued in both male and female progeny, as our preliminary data indicate some gender specific effects of gestational exposure to cocaine. While we anticipate that such studies will provide valuable scientific insights into the impact of prenatal cocaine on the function of the prefrontal cortex, we are hopeful that the studies in which the deficits are reversed pharmacologically will have positive social and economical repercussions by providing leads to the logical choices of drugs, and development of new drugs, to treat the detrimental effects of prenatal cocaine exposure.