Opioid Control of Identified Midbrain GABAergic Synapses

阿片类药物对中脑 GABA 能突触的控制

基本信息

批准号：
8633027
负责人：
HOWARD L FIELDS
金额：
$ 35.49万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8633027
关键词：
Acute Addictive Behavior Agonist Alcoholism Animals Bathing Behavior Binge Eating Cations Cell Nucleus Cells Chronic Clinical Data Development Disease Disinhibition Drug Addiction Electrophysiology (science)Elements Exhibits Exposure to Globus Pallidus Grant In Vitro Individual Inhibitory Synapse Investigation Knowledge Label Lead Light Limbic System Long-Term Potentiation Measurement Mediating Methods Midbrain structure Modeling Morphine Motivation Neurons Neurotransmitters Nucleus Accumbens Opioid Opioid Receptor Pharmacological Treatment Physiological Play Population Presynaptic Receptors Presynaptic Terminals Probability Property Psychological reinforcement Rattus Relative (related person)Rewards Rhodopsin Role Slice Source Structure Synapses Synaptic Receptors Synaptic plasticity Techniques Tracer Ventral Tegmental Area Viral Virus Diseases Whole-Cell Recordings base design dopaminergic neuron extracellular gamma-Aminobutyric Acid improved in vivo mu opioid receptors neural circuit novel novel strategies optogenetics patch clamp postsynaptic receptor relating to nervous system research study synaptic function tool

项目摘要

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.

描述（由申请人提供）：中脑腹侧被盖区（VTA）的多巴胺（DA）神经元在阿片类药物的奖励和增强作用中发挥重要作用。在 VTA 内，作用于 mu 阿片受体的阿片类药物抑制 GABA 的释放，从而导致 DA 神经元的去抑制（Johnson 和 North，1992a）。然而，VTA DA 神经元上的 GABA 突触不仅来自局部 GABA 能神经元，而且还来自外部来源，至少其中一些可能对阿片类药物敏感。 VTA 神经元抑制的两个主要外部来源来自伏隔核 (NAc) 和腹侧苍白球 (VP)，这两者都与阿片类药物奖赏密切相关。这些输入尚未明确定义，主要是由于隔离各个连接的技术挑战。然而，我们对阿片类药物奖励背后的神经回路的理解需要对这些 VTA 传入神经的突触特性进行彻底的研究。在这笔资助中，我们将利用最近开发的光遗传学工具，结合中脑切片中 VTA 神经元的全细胞膜片钳电生理学，独立激活 NAc 或 VP 产生的轴突末端。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慢性阿片类药物暴露的调节。此外，通过将这种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 VTA 内这些传入神经的详细微电路。这些研究提供的数据将为开发基于边缘系统功能的电路模型提供关键信息。