Kv7 channels and heavy alcohol drinking

Kv7通道和酗酒

基本信息

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
项目类别：
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

项目摘要

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. 总结/摘要过量饮酒（乙醇）是酒精使用障碍患者的一个标志特征（澳元）和形成酒精依赖的危险因素。经常共存的情绪和焦虑障碍使用 AUD 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 批准的药物对普通人群无效，而且也不针对合并症。这表明我们对导致过度饮酒的神经机制的理解存在相当大的差距及其共病神经精神疾病。深入了解促进的神经生物学因素过量的乙醇摄入和负面情感障碍可能会导致新疗法的开发降低复发率的策略。在之前的资助期间，我们的研究表明 KV7 通道是减少饮酒的目标，特别是对于具有高饮酒表型的啮齿动物。有新兴的有证据表明 KV7 通道是人类和啮齿动物负面情感行为的中介。在与这些结果一致，我们的初步数据为 KV7 通道调节提供了额外的证据与消极情感状态相关的行为。由于 KV7 通道在调节中的重叠作用内在兴奋性、酒精摄入量和负面情感行为，我们研究的长期目标是了解 KV7 通道中由过量酒精引起并驱动过量酒精的电路和细胞特异性适应饮酒和情感障碍。我们对这项资助的总体假设是 KV7 的下调渠道驱动内在兴奋性、过度饮酒和适应不良行为的可塑性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 KV7 通道- 前额皮质、伏隔核和特定回路和亚群的依赖性适应腹侧被盖区投射神经元在发育、维持和戒断过程中小鼠过量饮酒。此外，我们还将确定KV7通道激活剂瑞替加滨的能力扭转这些适应。这些研究将探索位于以下位置的 KV7 通道的形态适应：过量饮酒产生的轴突起始段。目标 3 的研究旨在确定 KV7 通道的适应在过程中导致负面情感障碍发展的作用戒除过量饮酒。拟议的研究将表征细胞和电路特定的投射神经元的适应导致过量乙醇摄入和负面情感行为。总的来说，这些临床前研究的结果将提供证据表明 KV7 通道在特定的神经电路是减少饮酒和神经精神疾病症状的目标与澳元共病。