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: 10554284
• 负责人: KEVIN D WICKMAN
• 金额: $ 34万
• 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/10554284
• 关键词: Ablation; Abstinence; Adaptive Behaviors; Alcohol consumption; Alcohol withdrawal syndrome; Alcoholic Intoxication; Alcohols; Amygdaloid structure; Anxiety; Association Learning; Behavior; Behavioral; Brain region; Clinical Data; Cocaine; Cognitive deficits; Collaborations; 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; 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; 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; pharmacologic; 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.

项目概要 酒精中毒和戒断的反复循环促进了调节情绪的大脑区域的适应， 这些适应被认为会促进哮喘焦虑和认知。 缺陷和渴望——酒精使用障碍（AUD）的标志，共同促进强迫性药物—— 寻求行为，增加旧病复发的可能性，并阻碍适应性行为的发展 尽管 AUD 的治疗选择有限，但临床前和临床数据已经表明。 人们对 GABAB 受体（GABABR）作为治疗干预的潜在靶点产生了兴趣 减少对酒精的渴望并减少酒精摄入量该项目的重点是乙醇引起的。 基底杏仁核 GABABR 依赖性信号传导的适应——焦虑的关键基质 与奖励和厌恶经历相关的学习使用两种不同的乙醇暴露模型。 通过重复的中毒循环，我们发现体细胞树突 GABABR 依赖性信号传导在 小鼠 BA 的主要神经元，在最后一次乙醇暴露后 3-4 天测量。 在外侧杏仁核的主要神经元或内侧前额叶/前边缘的锥体神经元中未见 皮质，也不是由重复的可卡因引起的。这种适应可归因于 G 蛋白门控的抑制。 内向矫正 K+ (GIRK) 通道活动，已知的焦虑相关行为和联想的决定因素 该项目的目标是了解显着特征和机制以及 乙醇诱导的 GIRK 通道活性抑制的神经生理学和行为学意义 BA 主要神经元。两个相互关联的目标是：（1）阐明乙醇的机制。 拟议的研究将采用离体技术。 电生理学、免疫电子显微镜和神经元特异性病毒操作来检验这一假设 乙醇诱导的 BA 主神经元 GIRK 通道活性抑制是由 GIRK3 亚基依赖性 GIRK 通道内化 (2) 了解下游。 拟议的研究将探讨 GIRK 通道可塑性的神经生理学和行为影响。 BA 主要神经元中 GIRK 通道活性抑制的影响，检验以下假设： 足以激发离散投影 BA 中谷氨酸能神经传递的适应。 适应与焦虑相关的行为、联想（恐惧）学习和自愿的后果 GIRK 病毒基因抑制后，将在未接触过乙醇的小鼠中评估乙醇消耗量 BA 主要神经元的通道活动 摘要：该项目利用了 BA 主要神经元的互补专业知识。 经验丰富的团队以及定制研究工具的可用性，可以调查以前未描述的 乙醇诱导的神经适应涉及对焦虑相关行为和联想的已知影响 成功完成该项目可能会产生治疗 AUD 的干预措施的新目标。