Cocaine and Brain Development

可卡因与大脑发育

• 批准号: 7472554
• 负责人: PRADEEP G BHIDE
• 金额: $ 32.58万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7472554
• 关键词: Agonist; Attention; Attenuated; Binding Sites; Biological Assay; Brain; CREB1 gene; Cells; Cerebral cortex; Cerebrum; Clinical Research; Cocaine; Cocaine Abuse; Cyclic AMP; DARPP 32; Development; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Economics; Electroporation; Embryo; Equilibrium; Event; Fetal Cocaine Exposure; Goals; Immigration; Impairment; Knockout Mice; Language Development; Learning; Left; Link; Mediating; Messenger RNA; Molecular; Mus; Neurons; Neurotransmitters; Phosphorylation; Pregnant Women; Preparation; Protein Binding; Public Health; Receptor Activation; Receptor Gene; Receptor Signaling; Recommendation; Reporting; Role; Signal Transduction; Slice; Study Section; Suggestion; System; Testing; Thinking; Wild Type Mouse; base; brain behavior; clinically relevant; day; density; fetal; gain of function; gamma-Aminobutyric Acid; insight; loss of function; maternal cocaine abuse; migration; monoamine; novel; protein expression; receptor; receptor binding; research study; response

DESCRIPTION (provided by applicant): The long term goals of the project are to determine if the effects of maternal cocaine abuse on fetal brain development are mediated by impairment of dopamine receptor signaling mechanisms. The specific goal of the current proposal is to examine if cocaine-induced impairment of dopamine receptor signaling contributes to deficits in neuronal migration in mouse embryos. Prenatal cocaine exposure appears to decrease GABA neuron migration from the ganglionic eminence to the cerebral wall in the embryonic mouse brain. Dopamine receptor activation also influences this migration. Prenatal cocaine exposure impairs dopamine receptor signaling. Therefore, we hypothesize that prenatal cocaine exposure interferes with GABA neuron migration from the ganglionic eminence to the cerebral wall by impairing dopamine receptor signaling mechanisms. We propose 3 Specific Aims to test our hypothesis. Specific Aim 1 will examine cocaine-induced changes in dopamine receptor signaling by quantitative analysis of receptor mRNA, protein, binding sites, agonist- induced cyclic AMP synthesis, phosphorylation of CREB and DARPP 32. Specific Aim 2 will determine if the deficits in GABA neuron migration produced by the cocaine exposure can be restored by electroporation of dopamine receptor constructs into neurons of the ganglionic eminence. Specific Aim 3 will use dopamine receptor knockout mice and a combination of loss and gain of function assays to confirm the role of these receptors in neuronal migration. The GABA neurons that migrate from the ganglionic eminence to the cerebral wall establish inhibitory circuits throughout the cerebral cortex. Clinical studies show that prenatal cocaine exposure causes lasting deficits in GABA-mediated functions, such as attention, language development and learning. Imbalance in the dopaminergic system of the developing brain also can cause similar impairments. Therefore, the focus of the proposed experiments on GABA neuron migration, gestational cocaine exposure and dopamine receptor signaling has significant clinical relevance. Cocaine abuse by pregnant women continues to be a major public health and socio-economic concern. Yet cellular and molecular mechanisms of cocaine's action on the developing brain are incompletely understood. The proposed studies promise novel insights into the mechanism of cocaine's action on fetal brain development by examining the link between cocaine, dopamine and development of GABA circuits.

描述（由申请人提供）：该项目的长期目标是确定母体可卡因滥用对胎儿大脑发育的影响是否由多巴胺受体信号传导机制的损害介导。目前建议的具体目标是检查可卡因诱导的多巴胺受体信号传导障碍是否有助于小鼠胚胎神经元迁移的缺陷。胎儿期可卡因暴露似乎减少GABA神经元从神经节隆起迁移到胚胎小鼠脑的大脑壁。多巴胺受体活化也影响这种迁移。产前可卡因暴露损害多巴胺受体信号传导。因此，我们推测，产前可卡因暴露干扰GABA神经元迁移从神经节隆起的大脑壁，通过损害多巴胺受体信号传导机制。我们提出了3个具体目标来验证我们的假设。具体目标1将通过定量分析受体mRNA、蛋白质、结合位点、激动剂诱导的环AMP合成、CREB和DARPP 32的磷酸化来检查可卡因诱导的多巴胺受体信号传导的变化。具体目标2将确定是否可以通过将多巴胺受体构建体电穿孔到神经节隆起的神经元中来恢复由可卡因暴露产生的GABA神经元迁移的缺陷。具体目标3将使用多巴胺受体敲除小鼠和功能丧失和获得试验的组合来确认这些受体在神经元迁移中的作用。从神经节隆起迁移到大脑壁的GABA神经元在整个大脑皮层建立抑制回路。临床研究表明，产前可卡因暴露会导致GABA介导的功能，如注意力，语言发育和学习的持久缺陷。发育中的大脑多巴胺能系统的不平衡也会导致类似的损伤。因此，对GABA神经元迁移、妊娠期可卡因暴露和多巴胺受体信号传导的拟议实验的关注具有显著的临床相关性。孕妇滥用可卡因仍然是一个重大的公共卫生和社会经济问题。然而，可卡因对发育中的大脑作用的细胞和分子机制还不完全清楚。拟议的研究通过检查可卡因，多巴胺和GABA回路发育之间的联系，有望对可卡因对胎儿大脑发育的作用机制产生新的见解。