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) 是一个重大的公共卫生问题，具有巨大的社会和经济影响。目前 FDA 批准的治疗 AUD 的药物疗法存在有害的副作用，并且仅对一小部分个体有效。这表明迫切需要改进药物。新的证据表明，抗惊厥药是治疗 AUD 患者的一类很有前途的药物。我们的初步数据表明，抗惊厥药瑞替加滨显着减少了两种自愿饮酒的啮齿动物模型的饮酒量。 Retigabine 是一种 KCNQ (Kv7) 电压依赖性 K+ 通道正调节剂，经 FDA 批准用于治疗部分性癫痫发作。在中枢神经元中，Kv7 通道在接近静息膜电位的电压下显示激活，并且是大脑中 M 电流 (IM) 的分子组成。 IM 激活对于细胞复极化、微调静息膜电位以及控制动作电位的产生和频率非常重要。先前的证据表明，急性酒精暴露会抑制腹侧被盖区 (VTA) 多巴胺和 CA1 锥体神经元的 IM。在果蝇中，Kv7 通道与急性酒精引起的记忆障碍和对急性酒精镇静作用的耐受性有关。最近的证据还证明了 Kv7 通道在突触可塑性和认知中的作用。众所周知，长期接触酒精会参与与突触可塑性相关的神经机制。然而，慢性饮酒是否影响 Kv7 通道表达或功能尚不清楚。初步证据表明，长期饮酒会改变伏隔核 (NAc) 中 Kv7.2 通道的表面运输。有趣的是，NAc 中的 Kv7.2 通道蛋白和转录物水平与自愿饮酒呈负相关。生物信息学分析还表明，编码 Kv7 通道的基因包含在小鼠饮酒的复制 QTL 的支持区间中。因此，我们的初步数据已将 Kv7 通道确定为可以影响自愿饮酒的有希望的分子靶点。此外，这些结果表明，长期饮酒会改变 Kv7 通道表达。设计了三个具体目标来检验该提案的总体假设，即 Kv7 通道是自愿饮酒的关键调节器。我们提出了一种利用生物化学、电生理学、药理学和小鼠转基因模型的多方面方法来确定：A) NAc、背内侧纹状体 (DMS) 或 VTA 中 Kv7 通道的正向调节是否可以减少饮酒（目标 1），B)突变体和转基因小鼠中 Kv7 通道功能的改变会影响饮酒量（目标 2），C) 长期饮酒会改变 NAc、DMS 和 VTA 中的 Kv7 通道功能和表达（目标 3）。这些研究将增进我们对酒精相关神经适应的了解，并反过来帮助我们在日益复杂的水平上理解 Kv7 通道在饮酒中的作用。