Opioid Control of Identified Midbrain GABAergic Synapses

阿片类药物对中脑 GABA 能突触的控制

• 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
• 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

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强化作用中起重要作用。在VTA内，阿片作用于mu阿片受体抑制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，也来自外部来源，至少其中一些可能对阿片类药物敏感。伏隔核（NAc）和腹侧pallidum （VP）是VTA神经元受到抑制的两个主要外部来源，它们都与阿片奖赏密切相关。这些输入尚未得到很好的定义，主要是由于隔离单个连接的技术挑战。然而，我们对阿片奖赏背后的神经回路的理解需要对这些VTA传入事件的突触特性进行彻底的研究。在本次资助中，我们将利用最近开发的光遗传学工具，结合中脑VTA神经元的全细胞膜片钳电生理学，独立激活由NAc或VP产生的轴突终端。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内这些传入事件的详细微电路。这些研究提供的数据将为边缘系统功能的电路模型的发展提供关键信息。