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MODULATION OF DOPAMINE AUTORECEPTOR FUNCTION BY COCAINE

可卡因对多巴胺自身受体功能的调节

基本信息

批准号：
6329138
负责人：
KAREN L O'MALLEY
金额：
$ 21.58万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-02-01 至 2002-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6329138
关键词：
cell line cocaine dopamine dopamine receptor membrane channels molecular cloning neurons neurotransmitter biosynthesis neurotransmitter metabolism neurotransmitter transport receptor coupling receptor expression receptor sensitivity synapses tissue /cell culture transfection

项目摘要

DESCRIPTION (Applicant's Abstract): The long term goal of this project is to define the consequences of the interaction of cocaine with presynaptic dopaminergic systems. Many of the behavioral effects of cocaine are attributed to its ability to block the reuptake of dopamine in mesolimbic neurons. Consequently, increased extracellular dopamine may enhance postsynaptic transmission and/or modulate presynaptic dopamine receptors known to inhibit neurotransmitter synthesis as well as further release. The specific aim of this application is to dissect this system by focussing on presynaptic events associated with cocaine's purported modulation of dopamine autoreceptors. Towards this end, model neuronal systems have been engineered by transfecting immortalized mesencephalic dopamine producing cell lines with cloned D2 and D3 receptors. To test the hypothesis that the D2-like receptors subserve different autoreceptor roles, the transfected cell lines are being systematically tested for receptor mediated effects on synthesis and release. Previously we have shown that agonist stimulation of D2 and D3 receptors leads to subtype specific reductions in dopamine release and synthesis. These data imply specific roles for each receptor and suggest the effects of cocaine may vary depending upon receptor subtype. Studies outlined in this proposal will 1 ) test the hypothesis that the differential autoreceptor effects of D2 and D3 receptors are due to distinct coupling mechanisms; 2) determine the mechanistic basis for D3 desensitization; 3) test the hypothesis that in primary cultures of neurons the dopamine D2 receptor subtype can serve all these functions: modulation of firing rate, dopamine synthesis and dopamine release; and 4) test the acute and chronic effects of cocaine on autoreceptor function in transfected cell lines and primary dopaminergic cultures. Taken together these studies will significantly extend our ongoing efforts to understand the complex receptor/presynaptic effector interactions involved in the reinforcing and behavioral sensitization effects of cocaine.

描述（申请人摘要）：该项目的长期目标是确定可卡因与突触前多巴胺能系统的相互作用。许多可卡因的行为效应归因于它能够阻断中脑边缘神经元对多巴胺的再摄取。因此，细胞外多巴胺可以增强突触后传递和/或调节突触后传递。已知抑制神经递质合成的突触前多巴胺受体以及进一步的释放。本申请的具体目的是通过关注与以下相关的突触前事件来剖析这个系统：可卡因对多巴胺自身受体的调节作用为此，模型神经元系统已经通过克隆永生化的具有克隆的D2和D3受体的中脑多巴胺产生细胞系。为了验证D2样受体在不同的细胞中发挥作用的假设，自身受体的作用，转染的细胞系正在系统地测试了受体介导的对合成和释放的影响。先前我们已经证明，D2和D3受体的激动剂刺激导致多巴胺释放和合成的亚型特异性减少。这些数据暗示了每个受体的特定作用，并表明可卡因的作用可以根据受体亚型而变化。本提案概述的研究将1）测试的假设，即差异自身受体的影响， D2和D3受体是由于不同的偶联机制; 2）确定 D3脱敏的机制基础; 3）检验假设，多巴胺D2受体亚型神经元的原代培养物可以满足所有需要这些功能：调节放电率，多巴胺合成和多巴胺释放;和4）测试可卡因的急性和慢性影响转染细胞系中的自身受体功能和原发性多巴胺能 cultures. 这些研究将大大扩展我们的目前正在努力了解复杂的受体/突触前效应器参与强化和行为敏化的相互作用可卡因的影响。