Dissecting Mechanisms of GABAB-GIRK Plasticity with Psychostimulants

解析精神兴奋剂 GABAB-GIRK 可塑性的机制

基本信息

批准号：
8658970
负责人：
Stephen J Moss
金额：
$ 42.95万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8658970
关键词：
Acute Affect Agonist Alcoholism Amygdaloid structure Autistic Disorder Baclofen Behavior Binding Biochemistry Brain C-terminal Chronic Clinical Data Dependence Depressed mood Dopamine Down-Regulation Drug Addiction Drug usage Elements Ensure FDA approved GTP-Binding Proteins Glutamates Goals Grant Health Care Costs Hippocampus (Brain)Injection of therapeutic agent Lead Learning Medial Mediating Mental Depression Methamphetamine Modeling Molecular Molecular Genetics Mosses Mus Neurons Nucleus Accumbens Output Pathway interactions Perception Pharmaceutical Preparations Pharmacological Treatment Phosphorylation Physiological Physiology Potassium Potassium Channel Prefrontal Cortex Process Property Protein Dephosphorylation Protein phosphatase Proteins Publishing Regulation Regulatory Pathway Research Research Personnel Resistance Rewards Role Signal Transduction System Testing Ventral Tegmental Area addiction behavioral sensitization cost dopaminergic neuron drug of abuse drug reward effective therapy gamma-Aminobutyric Acid genetic regulatory protein improved innovation methamphetamine exposure motivated behavior mutant nervous system disorder neural circuit neurochemistry neuronal excitability novel novel strategies preclinical study preference psychostimulant public health relevance receptor receptor coupling receptor function research study response stimulant abuse structural biology synaptic inhibition tool

项目摘要

DESCRIPTION (provided by applicant): Addictive drugs usurp the brain's intrinsic mechanism for reward, leading to compulsive and destructive behaviors. While there have been significant advances in understanding the neurochemical and physiological changes in addiction, clinically effective treatments have eluded researchers. Remarkably, there are no FDA approved drugs for treating psychostimulant abuse. In the ventral tegmental area (VTA), the center of the brain's reward center, GABAergic inhibition controls the excitability of neurons. A primary component of the GABAergic inhibitory pathway is formed by GABAbeta receptors that couple to G protein-gated potassium (GIRK) channels. Studies show that an acute injection of psychostimulant in mice produces a robust depression of the GABAbeta receptor GIRK inhibitory pathway in VTA GABA neurons but not in DA neurons. This drug-evoked depression of GABAbetaR signaling in GABA neurons removes an intrinsic brake on GABA neuron firing that would result in enhanced GABA-mediated inhibition of DA neurons and potentially reducing reward perception. This acute effect of psychostimulants provides a unique opportunity learn how to control the VTA output through alterations in the levels of endogenously expressed GABAbeta-GIRK proteins in VTA GABA neurons. However, detailed pre-clinical studies are needed to better understand how adaptations in GABAbetaR-GIRK signaling in VTA GABA neurons affect the output of the VTA and motivated behavior. The main objectives of this project are to determine the role of phosphorylation of the receptor in this change of GABAbeta-GIRK signaling and assess whether down-regulation of GABAbeta receptor alters the addictive properties of psychostimulants. Specifically, we will (i) test the hypothesis that dephosphorylation of the receptor underlies the ability of psychostimulants to down regulate GABAbeta receptor activity in VTA GABA neurons, (ii) elucidate the structural and molecular interactions governing protein phosphatase 2A (PP2A) association with the GABAbeta receptor, and (iii) determine impact of GABAbeta-GIRK signaling in GABA neurons on VTA function and motivated behavior. The research team will use a comprehensive approach that combines molecular genetics, structural biology, biochemistry, physiology and behavior. The hypothesis that psychostimulants regulate synaptic inhibition by modulating GABAbeta receptor phosphorylation, a process that is dependent upon a fraction of PP2A directly associating with the receptor, is an innovative and untested model. The concept that the C terminal domain of the GABAbeta receptor serves as the epicenter for coordinating regulatory proteins for receptor function could provide the framework for understanding the molecular regulation of other GPCRs in the brain. Baclofen (Lioresal) is an agonist of the GABAbeta receptor and is being evaluated for treating alcoholism, addiction and autism. Selectively targeting the GABAergic inhibitory system as described here could lead to improved clinical use of baclofen and perhaps to new drugs for treating addiction and other neurological disorders.

描述（由申请人提供）：成瘾药物篡夺了大脑内在的奖赏机制，导致强迫性和破坏性行为。尽管在理解成瘾的神经化学和生理变化方面取得了重大进展，但临床上有效的治疗方法一直困扰着研究人员。值得注意的是，目前还没有 FDA 批准的药物用于治疗精神兴奋剂滥用。在腹侧被盖区（VTA），即大脑奖赏中心的中心，GABA能抑制控制着神经元的兴奋性。 GABA 能抑制途径的主要组成部分是由与 G 蛋白门控钾 (GIRK) 通道偶联的 GABAbeta 受体形成的。研究表明，给小鼠急性注射精神兴奋剂会强烈抑制 VTA GABA 神经元中的 GABAβ 受体 GIRK 抑制通路，但不会抑制 DA 神经元中的 GABAβ 受体 GIRK 抑制通路。这种由药物引起的 GABA 神经元中 GABAbetaR 信号传导的抑制消除了 GABA 神经元放电的内在制动，从而导致 GABA 介导的 DA 神经元抑制增强，并可能降低奖赏感知。精神兴奋剂的这种急性作用提供了一个独特的机会，了解如何通过改变 VTA GABA 神经元中内源性表达的 GABAbeta-GIRK 蛋白的水平来控制 VTA 输出。然而，需要详细的临床前研究来更好地了解 VTA GABA 神经元中 GABAbetaR-GIRK 信号的适应如何影响 VTA 的输出和动机行为。该项目的主要目标是确定受体磷酸化在 GABAbeta-GIRK 信号传导变化中的作用，并评估 GABAbeta 受体的下调是否会改变精神兴奋剂的成瘾特性。具体来说，我们将 (i) 检验这一假设，即受体的去磷酸化是精神兴奋剂下调 VTA GABA 神经元中 GABAbeta 受体活性能力的基础，(ii) 阐明控制蛋白磷酸酶 2A (PP2A) 与神经兴奋剂相关的结构和分子相互作用。 GABAbeta 受体，(iii) 确定 GABA 神经元中 GABAbeta-GIRK 信号传导对 VTA 功能和动机行为的影响。研究小组将采用结合分子遗传学、结构生物学、生物化学、生理学和行为学的综合方法。精神兴奋剂通过调节 GABAbeta 受体磷酸化来调节突触抑制的假设是一个创新且未经测试的模型，该过程依赖于 PP2A 的一部分直接与受体结合。 GABAβ 受体的 C 末端结构域作为协调受体功能调节蛋白的中心这一概念可以为理解大脑中其他 GPCR 的分子调节提供框架。 Baclofen (Lioresal) 是一种 GABAbeta 受体激动剂，目前正在评估其治疗酗酒、成瘾和自闭症的效果。如本文所述，选择性靶向 GABA 能抑制系统可能会改善巴氯芬的临床使用，并可能导致治疗成瘾和其他神经系统疾病的新药。