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Cocaine and Mesolimbic Dopamine Electrophysiology

可卡因和中脑边缘多巴胺电生理学

基本信息

批准号：
7074554
负责人：
Kuei-Yuan Tseng
金额：
$ 34.28万
依托单位：
ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-02-01 至 2008-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Cocaine addiction remains among the most significant health concerns in the United States. Understanding the mechanisms by which recreational use of cocaine leads to compulsive drug abuse is certain to enhance our ability to design better treatment strategies for cocaine addiction. The forebrain nucleus accumbens (NAc) has long been recognized as a critical structure involved in motivated behavior, including drug seeking and the reinforcing effects of drugs and other "natural rewards". This nucleus is comprised primarily of medium spiny neurons (MSNs) which serve as its only output source and are regulated by both afferent inputs and voltage-gated ion channels (VGICs). The present application seeks to continue studies designed to determine how DA and other neurotransmitters specifically modulate VGICs and how both channel activity and neurotransmitter modulation are altered by repeated cocaine administration and withdrawal. For all studies, we will use primarily whole-cell patch clamp recordings from acutely dissociated rat NAc neurons. The first specific aim will characterize further the modulation of whole-cell sodium current and alterations produced by repeated cocaine administration. Experiments will determine whether other drugs of abuse, like cocaine, decrease basal whole-cell sodium current density, whether DA modulates persistent Na+ currents and whether such currents and modulation are altered by repeated cocaine administration. Finally, we will determine whether metabotropic glutamate receptors (mGluRs), which have recently been found to be necessary for cocaine self-administration, might also modulate whole-cell Na+ currents. The second specific aim will determine the mechanisms by which repeated cocaine administration reduces basal whole-cell Ca2 current in NAc neurons and whether DA D2Rs and mGluR receptors alter Ca2+ currents, and if so, whether repeated cocaine treatment alters such modulation. The third specific aim will initiate studies designed to determine whether DA receptors modulate specific K+ conductances in NAc neurons and whether such modulation is altered by repeated cocaine treatment. We anticipate that delineation of the roles of DA-Rs and mGluRs in modulating specific VGICs and how such modulation is altered by repeated cocaine treatment will greatly advance our understanding of potential molecular targets for pharmacotherapy.

描述（由申请人提供）：可卡因成瘾仍然是美国最重要的健康问题之一。了解可卡因的娱乐性使用导致强迫性药物滥用的机制，肯定会提高我们设计更好的可卡因成瘾治疗策略的能力。前脑神经核（NAc）长期以来被认为是参与动机行为的关键结构，包括药物寻求和药物和其他“自然奖励”的强化效应。该核主要由中等多刺神经元（MSNs）组成，MSNs作为其唯一的输出源，并由传入输入和电压门控离子通道（VGIC）两者调节。本申请寻求继续设计用于确定DA和其他神经递质如何特异性调节VGIC以及通道活性和神经递质调节如何通过重复的可卡因施用和戒断而改变的研究。对于所有的研究，我们将主要使用急性分离的大鼠NAc神经元的全细胞膜片钳记录。第一个具体目标将进一步表征全细胞钠电流的调制和重复可卡因给药产生的改变。实验将确定是否滥用其他药物，如可卡因，降低基础全细胞钠电流密度，DA是否调节持续的Na+电流，以及这种电流和调制是否被重复可卡因给药改变。最后，我们将确定是否代谢型谷氨酸受体（mGluRs），最近被发现是必要的可卡因自我管理，也可能调节全细胞Na+电流。第二个具体目标将确定的机制，重复可卡因管理减少基础全细胞钙电流NAC神经元和DA D2 Rs和mGluR受体是否改变钙电流，如果是这样，是否重复可卡因治疗改变这种调制。第三个具体目标将启动研究，旨在确定是否DA受体调节特定的K+电导NAc神经元，以及是否这种调制被改变重复可卡因治疗。我们预计，DA-Rs和mGluRs在调节特定VGIC中的作用以及这种调节如何被重复可卡因治疗改变的描述将极大地促进我们对药物治疗潜在分子靶点的理解。