Dissecting Mechanisms of GABAB-GIRK Plasticity with Psychostimulants

解析精神兴奋剂 GABAB-GIRK 可塑性的机制

• 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
• 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

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）：成瘾药物篡夺大脑的内在机制的奖励，导致强迫和破坏性行为。虽然在理解成瘾的神经化学和生理变化方面取得了重大进展，但临床有效的治疗方法却一直困扰着研究人员。 值得注意的是，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），大脑的奖励中心，GABA能抑制控制神经元的兴奋性。 GABA能抑制途径的主要组分由与G蛋白门控钾（GIRK）通道偶联的GABA β受体形成。研究表明，在小鼠中急性注射精神兴奋剂在腹侧被盖区GABA神经元中产生对GABA β受体GIRK抑制通路的强烈抑制，但在DA神经元中不产生。 GABA神经元中GABA β R信号传导的这种药物诱发的抑制消除了GABA神经元放电的内在制动，这将导致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，可以了解如何通过改变VTA GABA神经元中内源性表达的GABAbeta-GIRK蛋白水平来控制VTA输出。 然而，需要进行详细的临床前研究，以更好地了解VTA GABA神经元中GABA β R-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GABA β-GIRK信号传导变化中的作用，并评估GABA β受体的下调是否会改变精神兴奋剂的成瘾特性。 具体而言，我们将（i）测试这样的假设，即受体的去磷酸化是精神兴奋剂下调VTA GABA神经元中GABA β受体活性的能力的基础，（ii）阐明蛋白磷酸酶2A（PP 2A）与GABA β受体相关的结构和分子相互作用，和（iii）确定GABA神经元中GABA β-GIRK信号传导对VTA功能和动机行为的影响。研究小组将采用综合方法，结合分子遗传学、结构生物学、生物化学、生理学和行为学。 精神兴奋剂通过调节GABA β受体磷酸化来调节突触抑制的假设是一个创新的和未经检验的模型，该过程依赖于与受体直接相关的PP 2A的一部分。GABA β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。 巴氯芬（利多卡因）是一种GABA β受体激动剂，正在评估用于治疗酗酒、成瘾和自闭症。选择性靶向GABA能抑制系统，如这里所描述的可能会导致改善巴氯芬的临床使用，并可能用于治疗成瘾和其他神经系统疾病的新药。