PRENATAL COCAINE ALTERS CORTICAL DOPAMINE FUNCTION

产前可卡因改变皮质多巴胺功能

• 批准号: 2713173
• 负责人: ROBERT Henry ROTH
• 金额: $ 19.85万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2713173
• 关键词: age difference; behavior test; behavioral /social science research tag; cocaine; cognition; dopamine; embryo /fetus toxicology; gender difference; laboratory rat; neurochemistry; prenatal stress; stress

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.

描述：（申请人摘要） 过去可卡因滥用数量的惊人增加 怀孕期间吸食可卡因的流行率反映了这十年的情况， 部分地区估计高达8%至30%。 因此，有 现在有相当多的儿童接触过 可卡因在其发展初期的影响。 可卡因 怀孕期间的使用似乎与多种 后代的神经行为异常。 虽然一些影响 胎儿接触可卡因在新生儿中出现短暂，有 有迹象表明可能会出现一些长期持续的赤字。 特别是， 注意力缺陷多动障碍（ADDH）的发病率似乎 产前接触可卡因后明显增加。 虽然这些 临床研究强烈表明妊娠期的有害影响 接触可卡因，需要对实验动物进行对照研究 为了更全面地了解怀孕期间使用可卡因的影响 并找到扭转赤字的方法。 这 该提案的总体假设，其强有力的初步数据是 提出，产前接触可卡因会扰乱大脑功能 多巴胺输入到后代的前额皮质，并且这样的 缺陷反映在认知缺陷上，这种缺陷在以下情况下最为明显： 紧张的条件。 我们建议使用敏感的方法来追求这一假设 用于研究给予大鼠后代的生化和行为测量 怀孕期间可卡因。 生化技术将包括体外和 突触前和突触后神经元活动的体内测量 前额皮质中的多巴胺能末端。 压力引起的改变 空间工作记忆的行为测量将通过以下方式进行评估 延迟交替任务中的表现。 压力会由以下原因引起 将大鼠暴露于致焦虑 B-咔啉药物或 紧张的嗅觉暗示。 产前暴露引起的异常 可卡因将在出生后 3 岁进行调查。 效果将会是 正如我们的初步数据表明的那样，在雄性和雌性后代中都进行了追求 妊娠期接触可卡因对性别有一些特定影响。 当我们 预计此类研究将提供有价值的科学见解 产前可卡因对前额皮质功能的影响，我们 希望研究能够扭转赤字 药理学上将产生积极的社会和经济影响 提供药物的合理选择和新药物的开发 药物，以治疗产前接触可卡因的有害影响。