PRENATAL COCAINE ALTERS CORTICAL DOPAMINE FUNCTION

描述：（申请人摘要） 过去一年中可卡因滥用的惊人增长 怀孕期间可卡因使用的流行率反映了十年来的变化， 估计在某些地区高达8%至30%。 因此， 现在有相当数量的儿童接触到 可卡因在其发展初期的作用。 可卡因 怀孕期间使用似乎与各种 后代的神经行为异常 虽然一些影响的 胎儿暴露于可卡因出现短暂的新生儿，有 这些迹象表明，可能会出现一些长期的赤字。 特别是 注意缺陷多动障碍（ADDH）的发病率似乎是 在产前接触可卡因后显著增加。 虽然这些 临床研究表明，妊娠的有害影响是非常明显的。 暴露于可卡因，需要在实验室动物中进行对照研究， 为了更全面地了解怀孕期间使用可卡因的影响， 对后代的影响，并找到扭转赤字的方法。 的 这一建议的总体假设，其中强有力的初步数据是 目前，产前暴露于可卡因可以扰乱功能， 多巴胺输入到后代的前额叶皮层，这样一个 缺陷反映在认知缺陷上，在以下情况下最明显 紧张的条件。 我们建议使用敏感的 生物化学和行为测量，以研究大鼠的后代， 怀孕期间服用可卡因 生物化学技术将包括体外和 在体内测量突触前和突触后的神经元活动， 前额叶皮层的多巴胺能末梢 应激诱导的改变 空间工作记忆的行为测量将通过以下方式进行评估： 在延迟交替任务中的表现。 压力将由 将大鼠暴露于致焦虑B-咔啉药物或 紧张的嗅觉线索 产前暴露诱发流产 可卡因将在出生后3个年龄进行研究。 效果会 我们的初步数据显示， 妊娠期接触可卡因对性别的影响 虽然我们 预计这些研究将提供有价值的科学见解， 产前可卡因对前额叶皮层功能的影响，我们 希望这些研究能够扭转 这将产生积极的社会和经济影响， 为药物的合理选择提供线索，并开发新的 药物，以治疗产前可卡因暴露的有害影响。

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.