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Kir 3 Channel Subunits in Drug Abuse with GABAB Agonists

GABAB 激动剂药物滥用中的 Kir 3 通道亚基

基本信息

批准号：
7587306
负责人：
Paul A Slesinger
金额：
$ 45.42万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-05-15 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7587306
关键词：
Acute Address Affect Agonist Asses Brain Butyric Acids Cells Collaborations Communities Coupling Dependence Designer Drugs Dopamine Drug Addiction Drug Delivery Systems Drug abuse Esthesia Event G-Protein-Coupled Receptors GABA Receptor GIRK1 subunit, G protein-coupled inwardly-rectifying potassium channel GIRK2 subunit, G protein-coupled inwardly-rectifying potassium channel GIRK3 subunit, G protein-coupled inwardly-rectifying potassium channel GTP-Binding Protein Regulators GTP-Binding Proteins Human Image Imaging Techniques Institutes Laboratories Lead Link Mediating Methodology Modeling Molecular National Institute of Drug Abuse Neurobiology Neurons Output Paper Pharmaceutical Preparations Physiology Play Potassium Property Publishing RGS Proteins Reagent Relapse Rewards Role Science Slice Switzerland System Techniques Transgenic Mice Universities Ventral Tegmental Area Viral Work addiction club drug craving dopaminergic neuron drug of abuse fluorescence imaging frontier gamma-Aminobutyric Acid mesolimbic system novel patch clamp programs public health relevance receptor research study response success two-photon

项目摘要

We propose to study the acute effects of the increasingly popular designer drug gamma-hydroxy butyric acid (GHB) on neurons in the ventral tegmental area (mesolimbic dopamine system). The actions of GHB are mediated through G protein-coupled receptors (GPCRs)of the GABAB type, activating downstream effectors, such as G protein-gated inwardly rectifying potassium (Kir3 or GIRK) channels. We hypothesize that specific combinations of GIRK channels play a primary role in mediating acute rewarding effects of GABAg receptor agonists on mesolimbic dopamine system. We will (1) elucidate the role of regulator of G-protein signaling (RGS) proteins in modulating the coupling efficiency of GABAB receptors, (2) asses the role of GIRK channel subunits (GIRK1, GIRK2, and GIRK3) on setting the coupling efficiency of GABAB receptors in dopamine and GABA neurons of the VTA, and (3) determine single-channel properties and rules of assembly of heteromeric GIRK channels in the VTA. We will use a two-pronged approach ¿ a systems level approach involving patch-clamp recordings and two-photon imaging in acute brain slices from wild-type, GIRK- deficient, and transgenic mice; and a cellular approach, involving patch-clamp recordings and advanced imaging techniques from GIRK channels expressed in heterologous cells and in cultured neurons of the VTA. Together, these studies will reveal the cellular and molecular events underlying GIRK channel assembly and coupling to GABAs receptors in the brain, as well as elucidate the role of GIRK channels in determining the efficacy of GHB and related drugs in the brain. Public health relevance. Drug abuse is a USand world-wide problem affecting millions of people. Drugs of abuse impart strong sensations of reward, which may lead to repetitive drug administration, dependence and addiction. Addiction is characterized by relapse in response to uncontrollable cravings. The initial rewarding effects as well as the cravings are associated with the activation of the mesolimbic dopamine system. The abuse of GHB has increased dramatically over the last few years. By unraveling the role of GIRK channels in mediating GHB actions, we may reveal targets for new drugs that either directly activate these channels or alter the coupling efficiency to GPCRs. Such an approach may establish GIRK channels as formidable drug targets for treating addiction.

我们建议研究日益流行的设计药物-羟基丁酸的急性效应