Kv7 Channels and Heavy Alcohol Consumption

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AUDS的药物疗法存在有害的副作用，并且只对一小部分人有效。这意味着有必要改进药物治疗。新出现的证据表明，抗惊厥药物是治疗AUDS患者的一种很有前途的药物。我们的初步数据显示，在两种自愿饮酒的啮齿动物模型中，抗惊厥药瑞格他滨显著减少饮酒。瑞替加宾是一种KCNQ(KV7)电压依赖性钾通道正性调节剂，FDA批准用于治疗部分性癫痫发作。在中枢神经元，KV7通道在接近静止膜电位的电压下表现出激活，是大脑M-电流(IM)的分子组成。IM的激活对于重新极化细胞、微调静息膜电位以及控制动作电位的产生和频率是重要的。已有证据表明，急性酒精暴露可抑制腹侧被盖区(VTA)、多巴胺和CA1区锥体神经元的IM。在果蝇中，KV7通道与急性酒精诱导的记忆损伤和对急性酒精暴露的镇静效应的耐受有关。最近的证据也证明了KV7通道在突触可塑性和认知中的作用。众所周知，慢性酒精暴露会触发与突触可塑性相关的神经机制。然而，长期饮酒是否会影响KV7通道的表达或功能尚不清楚。初步证据表明，长期饮酒改变了伏隔核(NAC)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通道的基因包括在小鼠饮酒的重复QTL的支持区间中。因此，我们的初步数据已经确定KV7通道是有希望的分子靶点，可以影响自愿饮酒。此外，这些结果还表明，长期饮酒改变了KV7通道的表达。设计了三个具体的目标来测试这一提议的总体假设，即KV7通道是自愿饮酒的关键调节因素。我们提出了一种多方面的方法，利用生物化学、电生理学、药理学和小鼠转基因模型来确定：A)正向调制NAC、背内侧纹状体(DMS)或VTA中的KV7通道是否可以减少饮酒(目标1)，B)突变和转基因小鼠中KV7通道功能的改变可以影响饮酒(目标2)，以及C)长期饮酒改变NAC、DMS和VTA中的KV7通道功能和表达(目标3)。这些研究将促进我们对酒精相关神经适应的了解，并反过来帮助我们在越来越复杂的水平上理解KV7通道在酒精饮酒中的作用。

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.