Kv7 Channels and Heavy Alcohol Consumption

Kv7 通道和重度酒精消耗

基本信息

批准号：
8760730
负责人：
PATRICK J. MULHOLLAND
金额：
$ 33.64万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
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：
2014-09-05 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8760730
关键词：
Action Potentials Acute Adverse effects Affect Alcohol consumption Alcohol withdrawal syndrome Alcohols Anticonvulsants Attenuated Biochemical Biochemistry Bioinformatics Brain Brain region Cells Chronic Clinical Cognition Consumption Corpus striatum structure Data Detergents Dopamine Drosophila genus Economic Burden Electrophysiology (science)Ensure FDA approved Frequencies Generations Genes Individual Injection of therapeutic agent Knowledge Ligands Membrane Membrane Potentials Memory impairment Molecular Molecular Target Mus Neurons Nucleus Accumbens Pharmaceutical Preparations Pharmacology Pharmacotherapy Potassium Channel Proteins Public Health Qualifying Rattus Relapse Research Personnel Resistance Rest Rodent Rodent Model Role Seizures Stimulus Surface Symptoms Synaptic plasticity Techniques Testing Transcript Transgenic Mice Transgenic Model Ventral Tegmental Area Wistar Rats addiction alcohol availability alcohol exposure alcohol related problem alcohol use disorder binge drinking chronic alcohol ingestion design drinking drinking behavior economic impact hippocampal pyramidal neuron improved mutant neuroadaptation neuromechanism new therapeutic target novel pre-clinical prevent public health relevance sedative social trafficking voltage

项目摘要

DESCRIPTION (provided by applicant): Alcohol use disorders (AUDs) are a major public health issue and have an enormous societal and economic impact. Current FDA-approved pharmacotherapies for treating AUDs suffer from deleterious side effects and are only effective in a subset of individuals. This signifies an essential need for improved medications. Emerging evidence suggests that anticonvulsants are a promising class of drugs for treating individuals with AUDs. Our preliminary data demonstrates that the anticonvulsant retigabine significantly reduces drinking in two rodent models of voluntary alcohol consumption. Retigabine is a KCNQ (Kv7) voltage-dependent K+ channel positive modulator that is approved by the FDA for treating partial onset seizures. In central neurons, Kv7 channels display activation at voltages close to the resting membrane potential and are the molecular composition of the M-current (IM) in brain. IM activation is important for repolarizing the cell, fine-tuning the resting membrane potential, and controlling action potential generation and frequency. Previous evidence has demonstrated that acute alcohol exposure inhibits IM in ventral tegmental area (VTA) dopamine and CA1 pyramidal neurons. In Drosophila, Kv7 channels have been implicated in acute alcohol-induced memory impairments and tolerance to the sedative effects of acute alcohol exposure. Recent evidence has also demonstrated a role for Kv7 channels in synaptic plasticity and cognition. Chronic alcohol exposure is known to engage neural mechanisms associated with synaptic plasticity. However, it is unknown if chronic alcohol consumption affects Kv7 channel expression or function. Preliminary evidence suggests that prolonged alcohol consumption alters surface trafficking of Kv7.2 channels in the nucleus accumbens (NAc). Interestingly, Kv7.2 channel protein and transcript levels in the NAc negatively correlated with voluntary alcohol intake. Bioinformatics analysis also demonstrated that genes that encode Kv7 channels are included in the support interval for replicated QTLs for alcohol consumption in mice. Thus, our preliminary data have identified Kv7 channels as promising molecular targets that can influence voluntary alcohol consumption. In addition, these results have demonstrated that prolonged alcohol consumption alters Kv7 channel expression. Three specific aims were designed to test the overarching hypothesis of this proposal that Kv7 channels are critical regulators of voluntary alcohol drinking. We have proposed a multifaceted approach using biochemistry, electrophysiology, pharmacology, and mouse transgenic models to determine if: A) positive modulation of Kv7 channels in the NAc, dorsomedial striatum (DMS), or VTA can reduce drinking (Aim 1), B) altered Kv7 channel function in mutant and transgenic mice can influence alcohol consumption (Aim 2), and C) prolonged drinking alters Kv7 channel function and expression in NAc, DMS, and VTA (Aim 3). These studies will advance our knowledge on alcohol-associated neuroadaptations and will in turn help us to understand, at an increasingly sophisticated level, the role of Kv7 channels in alcohol drinking.