Kv7 Channels and Heavy Alcohol Consumption

描述（由申请人提供）：酒精使用障碍（AUDs）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批准的用于治疗AUDs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。这意味着改进药物治疗的基本需求。新出现的证据表明，抗惊厥药是治疗aud患者的一种很有前途的药物。我们的初步数据表明，抗惊厥药雷加滨显著减少饮酒在两种啮齿类动物模型自愿饮酒。雷沙滨是一种KCNQ （Kv7）电压依赖性K+通道阳性调节剂，已被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，是脑内m电流（IM）的分子组成。IM激活对于细胞的复极化，微调静息膜电位，控制动作电位的产生和频率具有重要意义。先前的证据表明，急性酒精暴露可抑制腹侧被盖区（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。最近的证据也证明了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参与与突触可塑性相关的神经机制。然而，长期饮酒是否影响Kv7通道的表达或功能尚不清楚。初步证据表明，长时间饮酒会改变伏隔核（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酒精消耗复制qtl的支持区间内。因此，我们的初步数据已经确定Kv7通道是有希望的分子靶标，可以影响自愿饮酒。此外，这些结果表明，长期饮酒会改变Kv7通道的表达。设计了三个具体目标来测试该提案的总体假设，即Kv7频道是自愿饮酒的关键监管者。我们利用生物化学、电生理学、药理学和小鼠转基因模型提出了一种多方面的方法来确定：a) NAc、背内侧纹状体（DMS）或VTA中Kv7通道的积极调节是否可以减少饮酒（目的1）；B)突变和转基因小鼠中Kv7通道功能的改变是否可以影响酒精消耗（目的2）；C)长时间饮酒会改变NAc、DMS和VTA中的Kv7通道功能和表达（目的3）。这些研究将提高我们对酒精相关神经适应的认识，并将帮助我们在越来越复杂的层面上理解Kv7通道在饮酒中的作用。

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.