Kv7 Channels and Heavy Alcohol Consumption

Kv7 通道和重度酒精消耗

• 批准号: 9069373
• 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
• 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/9069373
• 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; Health; 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; sedative; social; trafficking; voltage

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.

描述（由申请人提供）：酒精使用障碍（AUD）是一个主要的公共卫生问题，并且具有巨大的社会和经济影响。当前通过FDA批准的用于治疗AUDS的药物疗法患有有害的副作用，并且仅在一个个体中有效。这表明需要改进药物的必要性。新兴的证据表明，抗惊厥药是一种有前途的药物，用于治疗用auds的个体。我们的初步数据表明，在两种自愿性饮酒模型中，抗惊nrestigabine显着降低了饮酒。 retigabine是KCNQ（KV7）电压依赖性K+通道阳性调节器，该调制器已获得FDA批准用于治疗部分发作性癫痫发作的。在中央神经元中，KV7通道在接近静止膜电位的电压下显示激活，是大脑中M-电流（IM）的分子组成。 IM激活对于重复细胞，微调静止膜电位以及控制动作电位的产生和频率很重要。先前的证据表明，急性酒精暴露会抑制腹侧换段区域（VTA）多巴胺和CA1锥体神经元的IM。在果蝇中，KV7通道与急性酒精诱导的记忆障碍和对急性酒精暴露的镇静作用的耐受性有关。最近的证据还表明，KV7通道在突触可塑性和认知中的作用。已知慢性酒精暴露会吸引与突触可塑性相关的神经机制。但是，尚不清楚慢性酒精消耗是否会影响KV7通道表达或功能。初步证据表明，延长酒精消耗会改变伏隔核（NAC）中KV7.2通道的表面运输。有趣的是，NAC中的KV7.2通道蛋白和转录水平与自愿性酒精摄入量负相关。生物信息学分析还表明，编码KV7通道的基因包含在复制的小鼠饮酒的支持间隔中。因此，我们的初步数据将KV7通道确定为可能影响自愿饮酒的有希望的分子靶标。此外，这些结果表明延长酒精消耗会改变KV7通道的表达。设计了三个具体目标，以检验该提议的总体假设，即KV7通道是自愿饮酒的关键调节者。我们已经提出了一种使用生物化学，电生理学，药理学和小鼠转基因模型的多方面方法，以确定是否：a）a）NAC中KV7通道的正调节，背侧纹状体（DMS）（DMS）或VTA或VTA可以减少饮酒（AIM 1），量子1）会在kv7频道中量化（aim 1），量会影响kv7通道饮用液体（b）饮用型饮酒型（b）饮用型饮酒型（a） NAC，DMS和VTA中的KV7通道函数和表达（AIM 3）。这些研究将提高我们对与酒精相关的神经适应的知识，进而帮助我们在越来越复杂的水平上了解KV7通道在饮酒中的作用。