Kv7 channels and heavy alcohol drinking

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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.