Opioid Control of Identified Midbrain GABAergic Synapses

描述(申请人提供)：中脑腹侧被盖区(VTA)中的多巴胺(DA)神经元在阿片类药物的奖赏和增强效应中发挥重要作用。在VTA内，作用于Mu阿片受体的阿片类物质抑制GABA的释放，从而导致DA神经元的去抑制(Johnson和North，1992a)。然而，GABA与VTA DA神经元的突触不仅来自局部的GABA能神经元，而且来自外部来源，至少其中一些可能对阿片类药物敏感。伏核(NAC)和腹侧苍白球(VP)是对VTA神经元产生抑制的两个主要外部来源，两者都与阿片类药物奖赏密切相关。这些输入没有得到很好的定义，这主要是由于隔离单个连接的技术挑战。然而，我们对阿片类奖赏背后的神经回路的理解需要对这些VTA传入的突触特性进行彻底的研究。在这项资助中，我们将利用最近发展的光遗传学工具，结合全细胞膜片钳电生理学，独立激活中脑片VTA神经元的NAC或VP产生的轴突终末。这将使我们能够比较和对比这两种输入，并确定它们如何受到急性和长期阿片类药物暴露的调节。此外，通过将这一强大的技术与来自特定投射目标的VTA神经元的逆行标记相结合，我们将能够确定这些传入在VTA内的详细微电路。这些研究提供的数据将为开发基于电路的边缘系统功能模型提供关键信息。 公共卫生相关性：阿片受体是治疗药物成瘾、酒精中毒和强迫进食的临床靶点。这些研究将加强我们对阿片受体如何控制潜在的动机和强化的神经回路的了解。准确了解阿片受体是如何改变成瘾行为的，将有助于改进对这些疾病的药物治疗。

DESCRIPTION (provided by applicant): Dopamine (DA) neurons in the midbrain ventral tegmental area (VTA) play an important role in the rewarding and reinforcing effects of opioids. Within the VTA, opioids acting at the mu opioid receptor inhibit the release of GABA, which leads to the disinhibition of DA neurons (Johnson and North, 1992a). However, GABA synapses onto VTA DA neurons arise not only from local GABAergic neurons, but also from extrinsic sources, at least some of which are likely to be sensitive to opioids. Two major external sources of inhibition onto VTA neurons arise from the nucleus accumbens (NAc) and the ventral pallidum (VP), both of which have been strongly implicated in opioid reward. These inputs have not been well defined, largely due to the technical challenge of isolating individual connections. Nevertheless, our understanding of the neural circuitry underlying opioid reward requires a thorough investigation of the synaptic properties of these VTA afferents. In this grant, we will make use of recently developed optogenetic tools to independently activate axon terminals arising from either the NAc or the VP in conjunction with whole cell patch-clamp electrophysiology from VTA neurons in midbrain slices. This will allow us to compare and contrast these two inputs and to determine how they are regulated by both acute and chronic exposure to opioids. In addition, by combining this powerful technique with retrograde labeling of VTA neurons from particular projection targets, we will be able to determine the detailed microcircuitry of these afferents within the VTA. The data provided by these studies will provide critical information for the development of circuit based models of limbic system function. PUBLIC HEALTH RELEVANCE: Opioid receptors are clinical targets for the treatment of drug addiction, alcoholism and compulsive eating. These studies will enhance our knowledge of how opioid receptors control the neural circuitry underlying motivation and reinforcement. Understanding precisely how opioid receptors alter addictive behaviors will lead to improved pharmacological treatments for these disorders.