Cocaine and Mesolimbic Dopamine Electrophysiology

描述（由申请人提供）：可卡因成瘾仍然是美国最严重的健康问题之一。了解娱乐性使用可卡因导致强迫性药物滥用的机制，肯定会提高我们设计更好的治疗可卡因成瘾策略的能力。前脑伏隔核（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强化效应以及其他“自然奖励”。该核主要由中棘神经元（msn）组成，作为其唯一的输出源，并受传入输入和电压门控离子通道（vgic）的调节。目前的申请旨在继续研究，以确定DA和其他神经递质如何特异性地调节vgic，以及反复给药和戒断可卡因如何改变通道活动和神经递质调节。在所有研究中，我们将主要使用急性游离大鼠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节和反复服用可卡因所产生的变化。实验将确定滥用其他药物（如可卡因）是否会降低基础全细胞钠电流密度，DA是否会调节持续的Na+电流，以及这种电流和调制是否会因反复服用可卡因而改变。最后，我们将确定代谢性谷氨酸受体（mGluRs）是否也可能调节全细胞Na+电流，该受体最近被发现是可卡因自我给药所必需的。第二个特定目标将确定反复服用可卡因减少NAc神经元基底全细胞Ca2电流的机制，以及DA D2Rs和mGluR受体是否改变Ca2+电流，如果是这样，反复服用可卡因是否会改变这种调节。第三个具体目标将启动旨在确定DA受体是否调节NAc神经元中特定的K+电导以及这种调节是否通过重复可卡因治疗而改变的研究。我们预计，DA-Rs和mGluRs在调节特异性vgic中的作用以及这种调节如何被反复可卡因治疗所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。

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.