Alcohol-related suppression of GIRK channel activity in the basal amygdala: a link to plasticity of glutamatergic neurotransmission and withdrawal-associated behavior?

与酒精相关的基底杏仁核 GIRK 通道活性抑制：与谷氨酸能神经传递的可塑性和戒断相关行为的联系？

• 批准号: 9885448
• 负责人: KEVIN D WICKMAN
• 金额: $ 33.79万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-20 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9885448
• 关键词: Ablation; Abstinence; Adaptive Behaviors; Alcohol consumption; Alcohol withdrawal syndrome; Alcoholic Intoxication; Alcohols; Amygdaloid structure; Anxiety; Behavior; Behavioral; Brain region; Clinical Data; Cocaine; Cognitive deficits; Custom; Data; Development; Electrophysiology (science); Ethanol; Fostering; Fright; GIRK3 subunit, G protein-coupled inwardly-rectifying potassium channel; GTP-Binding Proteins; Genetic Enhancement; Genetic Suppression; Glutamates; Goals; Immunoelectron Microscopy; Individual; Inhalation; Injections; Intervention; Intoxication; Knockout Mice; Lateral; Learning; Link; Literature; Measures; Medial; Mediating; Modeling; Molecular; Molecular Target; Moods; Mus; National Institute on Alcohol Abuse and Alcoholism; Neurons; Neurosciences; Pharmacology; Play; Predisposition; Process; Publishing; Relapse; Research; Research Personnel; Rewards; Role; Signal Transduction; Source; Techniques; Testing; Therapeutic Intervention; Viral; Withdrawal; Work; addiction; alcohol exposure; alcohol use disorder; anxiety-related behavior; classical conditioning; craving; disability; drug seeking behavior; experience; hippocampal pyramidal neuron; insight; interdisciplinary approach; interest; inward rectifier potassium channel; negative affect; neuroadaptation; neurophysiology; neurotransmission; new therapeutic target; optogenetics; pre-clinical; preventable death; receptor; targeted treatment; therapy design; tool; vapor; virus genetics

PROJECT SUMMARY Repeated cycles of alcohol intoxication and withdrawal foster adaptations in brain regions that regulate mood, learning, and goal-directed behavior. These adaptations are thought to promote heightened anxiety, cognitive deficits, and craving – hallmarks of alcohol use disorder (AUD) that collaborate to promote compulsive drug- seeking behavior, increase relapse susceptibility, and impede the development of adaptive behaviors that could support abstinence. Although treatment options for AUD are limited, preclinical and clinical data have generated interest in the GABAB receptor (GABABR) as a potential target for therapeutic interventions aimed at diminishing craving and reducing alcohol intake. The focus of this project is on an ethanol-induced adaptation in GABABR-dependent signaling in the basal amygdala – a key substrate of anxiety as well as learning related to rewards and aversive experiences. Using two distinct ethanol exposure models that yield repeated cycles of intoxication, we found that somatodendritic GABABR-dependent signaling is suppressed in principal neurons of the mouse BA, as measured 3-4 days after the last ethanol exposure. The adaptation is not seen in principal neurons of the lateral amygdala or pyramidal neurons of the medial prefrontal/prelimbic cortex, nor is it evoked by repeated cocaine. The adaptation is attributable to a suppression of G protein-gated inwardly rectifying K+ (GIRK) channel activity, a known determinant of anxiety-related behavior and associative learning. The goal of this project is to understand the salient features and mechanisms, as well as neurophysiological and behavioral implications, of the ethanol-induced suppression of GIRK channel activity in BA principal neurons. The two interrelated AIMs are to: (1) Elucidate mechanisms underlying the ethanol- induced suppression of GIRK channel activity. Proposed studies will employ techniques in ex vivo electrophysiology, immunoelectron microscopy, and neuron-specific viral manipulations to test the hypothesis that the ethanol-induced suppression of GIRK channel activity in BA principal neurons is mediated by the GIRK3 subunit-dependent internalization of GIRK channels. (2) Understand the downstream neurophysiological and behavioral implications of GIRK channel plasticity. Proposed studies will probe the implications of the suppression of GIRK channel activity in BA principal neurons, testing the hypothesis that it is sufficient to provoke adaptations in glutamatergic neurotransmission in discrete BA projections. In parallel, the consequences of the adaptation to anxiety-related behavior, associative (fear) learning, and voluntary ethanol consumption will be evaluated in ethanol-naïve mice, following viral genetic suppression of GIRK channel activity in BA principal neurons. Summary: This project leverages the complementary expertise of an experienced team, and the availability of custom research tools, to investigate a previously undescribed ethanol-induced neuroadaptation involving a known influence on anxiety-related behavior and associative learning. Successful completion of this project may yield new targets for interventions designed to treat AUD.

项目摘要 在调节情绪的大脑区域的酒精毒性和戒断促进适应的反复循环， 学习和目标指导的行为。这些适应被认为会促进焦虑，认知 缺陷和渴望 - 与酒精使用障碍的标志（AUD）合作以促进强迫性药物 - 寻求行为，提高继电器敏感性，并阻碍自适应行为的发展 尽管AUD的治疗选择有限，但临床前和临床数据具有 引起对GABAB受体（GABABR）的兴趣，作为针对治疗干预措施的潜在目标 减少渴望和减少酒精摄入量。该项目的重点是乙醇引起的 基本杏仁核中GABABR依赖性信号的适应 - 动画的关键基板以及 与奖励和厌恶经历有关的学习。使用两个不同的乙醇暴露模型 反复的中毒循环，我们发现somatendritic gababr依赖性信号被抑制 在上次乙醇暴露后3-4天测量的小鼠BA的主要神经元。改编是 在培养基前额叶/前膜的侧杏仁核或锥体神经元的主要神经元中未见 皮质，也不被重复的可卡因引起。适应归因于G蛋白门控的抑制 内向纠正K+（Girk）通道活动，这是一种已知与动画相关行为和关联的已知 学习。该项目的目的是了解显着特征和机制以及 神经生理学和行为意义，乙醇诱导的抑制GIRK通道活性 BA主要神经元。这两个相互关联的目的是：（1）阐明乙醇 - 诱导的抑制GIRK通道活性。拟议的研究将在离体中采用技术 电生理学，免疫电子显微镜和神经特异性病毒操纵以检验假设 乙醇诱导的BA主神经元中GIRK通道活性的抑制是由 GIRK3亚基依赖性内在化的内在化。 （2）了解下游 Girk通道可塑性的神经生理和行为意义。拟议的研究将探究 BA主神经元中抑制GIRK通道活性的含义，检验了它的假设 足以在离散BA预测中引起谷氨酸能神经传递的适应。并联， 适应与焦虑有关的行为，联想（恐惧）学习和自愿的后果 在病毒遗传抑制后，将在不含乙醇的小鼠中评估乙醇的消耗量 BA主神经元中的通道活动。摘要：该项目利用了一个完整的专业知识 经验丰富的团队以及自定义研究工具的可用性，以调查先前未描述的 乙醇引起的神经适应涉及对焦虑相关行为和联想的已知影响 学习。该项目的成功完成可能会为旨在治疗AUD的干预措施带来新的目标。