Kv7 channels and heavy alcohol drinking

Kv7通道和酗酒

• 批准号: 10470139
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10470139
• 关键词: Abstinence; Adult; Agreement; Alcohol consumption; Alcohol dependence; Alcohols; Anxiety; Anxiety Disorders; Attenuated; Automobile Driving; Axon; Behavior; Brain; Brain Diseases; Calcium; Cells; Characteristics; Chronic; Clinical Research; Complex; Coupled; DRD2 gene; Data; Development; Dopamine; Down-Regulation; Economic Burden; Electrophysiology (science); Emerging Technologies; FDA approved; Fiber; Funding; Gene Family; General Population; Genes; Goals; Grant; Heavy Drinking; Human; Individual; Intervention; Lead; Maintenance; Measures; Mediator of activation protein; Mental Depression; Molecular; Mood Disorders; Morphology; Mus; Neurobiology; Neurons; Nucleus Accumbens; Pattern; Pharmaceutical Preparations; Pharmacology; Phenotype; Photometry; Pre-Clinical Model; Prefrontal Cortex; Public Health; Publishing; Rattus; Regulation; Relapse; Reporter; Research; Rewards; Risk Factors; Rodent; Role; Synapses; Techniques; Testing; Time; Transgenic Organisms; Ventral Tegmental Area; Virus; affective disturbance; alcohol abuse therapy; alcohol availability; alcohol exposure; alcohol relapse; alcohol use disorder; anxiety-like behavior; associated symptom; awake; binge drinking; brain circuitry; chronic alcohol ingestion; comorbidity; depressive symptoms; design; drinking; drinking behavior; hippocampal pyramidal neuron; improved; in vivo; insight; maladaptive behavior; negative affect; neural circuit; neuromechanism; neuropsychiatric disorder; neuropsychiatric symptom; neuropsychiatry; novel; overexpression; preclinical study; prevent; promoter; psychosocial; reduce symptoms; relapse risk; social; therapeutic target; treatment strategy; validation studies; voltage

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.

7。摘要/摘要 过量酒精（乙醇）消费是饮酒障碍个体的标志性特征 （AUD）和发展酒精依赖的危险因素。情绪和焦虑症通常是合并症 使用AUD可以阻碍社会心理治疗干预措施，并增加复发的风险。而当前的FDA 批准的药物在普通人群中无效，它们也不针对合并症。 这是我们对驱动过量饮酒的神经机制的理解的巨大差距 及其合并症的神经精神疾病。深入了解促进的神经生物学因素 过度乙醇摄入和负面情感障碍可能导致新治疗的发展 降低复发率的策略。在上一个资金期间，我们的研究证明了KV7渠道 是减少饮酒的目标，尤其是在具有高饮用表型的啮齿动物中。有新兴 涉及KV7通道作为人类和啮齿动物负面情感行为的中介者的证据。在 与这些结果一致，我们的初步数据为KV7通道调节提供了其他证据 与负面情感状态有关的行为。由于KV7频道在调节中的角色重叠 内在的兴奋性，酒精摄入和负面情感行为，我们研究的长期目标是 了解在KV7通道中的电路和细胞特异性改编 饮酒和情感障碍。我们对这笔赠款的总体假设是KV7的下调 通道促进了内在兴奋性的可塑性，饮酒过量和适应不良的行为 有助于维持饮酒障碍。为了检验这一假设，目标1和2中的研究将使用 新兴技术，电生理和免疫荧光方法，以表征KV7通道 前额叶皮层，伏伏核和额叶皮层的特定电路和亚群的依赖适应 在开发和维持和戒酒期间 小鼠的酒精摄入过多。此外，我们将确定KV7通道激活剂Retigabine的能力 扭转这些改编。这些研究将探索位于KV7通道的形态适应 轴突初始片段由过量的酒精摄入产生。 AIM 3中的研究旨在确定 在KV7渠道中适应的作用有助于发展负面情感障碍 过多饮酒的禁欲。拟议的研究将表征细胞和电路特异性 投射神经元的适应，导致过度乙醇摄入和负面情感行为。 总的来说，这些临床前研究的发现将提供证据表明特定神经中的KV7通道 电路是减少饮酒和神经精神疾病症状的目标 与aud合并。