Kv7 channels and heavy alcohol drinking

7.总结/摘要 过量饮酒是酒精使用障碍患者的一个标志性特征 (AUD)也是酒精依赖的危险因素心境障碍和焦虑症通常是并存的 AUD患者可能会阻碍心理社会治疗干预并增加复发风险。虽然目前FDA 批准的药物在一般人群中无效，它们也不针对合并症。 这代表了我们对过度饮酒的神经机制的理解存在相当大的差距 及其共病的神经精神障碍。深入了解神经生物学因素， 过量的酒精摄入和消极的情感障碍可能会导致新的治疗方法的发展 降低复发率的策略。在上一个资助期，我们的研究表明，KV 7通道 是减少饮酒的目标，特别是在具有高饮酒表型的啮齿动物中。正在形成 有证据表明KV 7通道是人类和啮齿类动物负性情感行为的媒介。在 与这些结果一致，我们的初步数据为KV 7通道调节提供了额外的证据， 与消极情感状态有关的行为。由于KV 7通道在调节神经元的活动中的作用重叠， 内在兴奋性，酒精摄入量和负面情感行为，我们研究的长期目标是 了解KV 7通道中的回路和细胞特异性适应，这些适应是由过量酒精引起并驱动的 酗酒和情感障碍我们对这项研究的总体假设是，KV 7基因的下调可能是一个重要因素。 通道驱动内在兴奋性的可塑性，过度饮酒和适应不良行为， 有助于维持酒精使用障碍。为了检验这一假设，目标1和2中的研究将使用 新兴技术，电生理学和免疫荧光方法来表征KV 7通道- 在特定的电路和亚群的前额皮质，神经核， 腹侧被盖区投射神经元在发育、维持和戒断期间 小鼠过量饮酒。此外，我们将确定KV 7通道激活剂瑞替加滨 来逆转这些适应。这些研究将探索位于KV 7通道的形态适应， 酒精摄入过多产生的轴突起始段。目标3中的研究旨在确定 KV 7通道中的适应性有助于发展负性情感障碍， 避免过度饮酒。拟议的研究将表征细胞和电路特定 投射神经元中的适应性变化导致过量的乙醇摄入和消极的情感行为。 总的来说，这些临床前研究的结果将提供证据表明，特定神经元中的KV 7通道 回路是减少酒精消耗和神经精神疾病症状的目标， 与AUD共病。

7. SUMMARY/ABSTRACT Excessive alcohol (ethanol) consumption is a hallmark characteristic of individuals with alcohol use disorder (AUD) and a risk factor for developing alcohol dependence. Mood and anxiety disorders that are often comorbid with AUD can hinder psychosocial treatment interventions and increase the risk of relapse. While current FDA approved medications are not effective in the general population, they also do not target comorbid conditions. This represents a considerable gap in our understanding of the neural mechanisms driving excessive drinking and its comorbid neuropsychiatric disorders. Gaining insight into the neurobiological factors that facilitate excessive ethanol intake and negative affective disturbances may lead to the development of new treatment strategies for reducing relapse rates. In the previous funding period, our studies demonstrated that KV7 channels are a target for reducing alcohol drinking, especially in rodents with a high-drinking phenotype. There is emerging evidence implicating KV7 channels as a mediator of negative affective behaviors in humans and rodents. In agreement with these results, our preliminary data provide additional evidence for KV7 channel regulation of behaviors related to negative affective states. Because of the overlapping role for KV7 channels in regulating intrinsic excitability, alcohol intake, and negative affective behaviors, the long-term goal of our studies is to understand circuit- and cell-specific adaptations in KV7 channels that are caused by and drive excessive alcohol drinking and affective disturbances. Our overarching hypothesis of this grant is that down-regulation of KV7 channels drives plasticity of intrinsic excitability, excessive alcohol drinking, and maladaptive behaviors that contribute to the maintenance of alcohol use disorder. To test this hypothesis, studies in Aims 1 and 2 will use emerging technology, electrophysiological, and immunofluorescent approaches to characterize KV7 channel- dependent adaptations in specific circuits and subpopulations of prefrontal cortex, nucleus accumbens, and ventral tegmental area projection neurons during development and maintenance of and abstinence from excessive alcohol intake in mice. In addition, we will determine the ability of the KV7 channel activator retigabine to reverse these adaptations. These studies will explore morphological adaptations in KV7 channels located in the axon initial segment produced by excessive alcohol intake. Studies in Aim 3 are designed to determine the role that adaptations in KV7 channels contribute to the development of negative affective disturbances during abstinence from excessive alcohol drinking. The proposed research will characterize cell- and circuit-specific adaptations in projection neurons that contribute to excessive ethanol intake and negative affective behaviors. Collectively, the findings from these preclinical studies will provide evidence that KV7 channels in specific neural circuits are a target for reducing alcohol consumption and symptoms of neuropsychiatric conditions that are comorbid with AUD.