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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. 摘要/文摘