Ethanol Dependence Induced Changes in Dopamine Signaling in Basolateral Amygdala

乙醇依赖引起基底外侧杏仁核多巴胺信号的变化

基本信息

批准号：
9298374
负责人：
SARA RAULERSON JONES
金额：
$ 36.59万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-05 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9298374
关键词：
Abstinence Acute Alcohol abuse Alcohol withdrawal syndrome Alcoholism Amygdaloid structure Animals Anxiety Autoreceptors Behavior Behavioral Brain region Cell Nucleus Cells Characteristics Chronic Data Dependence Disinhibition Dopamine Dopamine Receptor Electrochemistry Electrophysiology (science)Emotions Ethanol Ethanol dependence Event Glutamates Goals Human In Vitro Lateral Life Measures Mediating Modeling Neurons Output Pathologic Periodicity Pharmaceutical Preparations Pharmacology Phase Physical Dependence Process Public Health Publications Rattus Receptor Signaling Recording of previous events Relapse Rewards Rodent Rodent Model Scanning Signal Transduction Stimulus Substantia nigra structure Synapses System Testing Therapeutic Intervention Ventral Tegmental Area Withdrawal Work addiction alcohol exposure alcohol relapse anxiety-like behavior base conditioned fear drinking experience experimental study in vivo innovation insight negative affect negative emotional state neural circuit neurobiological mechanism neurophysiology neurotransmission nonhuman primate optogenetics pars compacta patch clamp postsynaptic presynaptic problem drinker public health relevance receptor function response reuptake synaptic function withdrawal-induced anxiety

项目摘要

DESCRIPTION (provided by applicant): The overall goal of the current application is to understand the neurobiological mechanisms that help confer pathological behaviors like enhanced negative affect following ethanol physical dependence. Recent studies suggest that intrinsic lateral/basolateral amygdala (BLA) GABAergic neurons tightly control the expression of negative emotions including those expressed during withdrawal following chronic ethanol exposure. Dopaminergic inputs from the ventral tegmentum/substantia nigra pars compacta have been shown to regulate this GABAergic system and disinhibit BLA principal neurons which drive the expression of anxiety-like behaviors. Based on strong preliminary evidence, our proposed experiments will test the central hypothesis that ethanol dependence dis-inhibits BLA output by dysregulating dopaminergic modulation of these GABAergic neurons. We will test our central hypothesis and accomplish our overall goal by utilizing a well- established rat model of chronic ethanol exposure and by integrating optogenetic, pre- and post-synaptic dopamine neurophysiology, and behavioral experimental approaches. The BLA has been extensively implicated as an important regulatory component of the neural circuitry controlling both anxiety-like behavior during withdrawal from chronic ethanol exposure as well as reward-seeking in drug-naïve and -exposed animals. Specific Aim 1 will test our central hypothesis hypothesis by examining presynaptic dopamine function during withdrawal from ethanol dependence. We will directly measure DA release and reuptake in vitro by integrating in vitro fast-scan cyclic voltammetry with optogenetic control of DA release and chronic ethanol exposure. We hypothesize that, based on our previous publications, chronic ethanol exposure will differentially modulate basal or `tonic' DA levels and phasic DA release to ultimately enhance DA signaling. Specific Aim 2 will examine how postsynaptic DA receptor function is altered in the BLA using in vitro whole cell patch clamp electrophysiology with innovative optogenetic approaches to measure postsynaptic DA receptor signaling. Our working hypothesis is that ethanol physical dependence will increase postsynaptic D1- and D2-like DA receptor signaling such that DA-mediated inhibition of GABAergic function is up-regulated. Specific Aim 3 will place the detailed cellular effects of dependence on DA signaling within a whole-animal context by integrating optogenetic control of DA release with in vivo measures of BLA-dependent behaviors. Our working hypothesis is that dependence-related changes in dopamine neurotransmission and signaling ultimately control withdrawal-dependent anxiety-like behavior. The proposed work employs a unique and highly integrated experimental approach to provide unparalleled insight into the neurobiological mechanisms governing the negative reinforcing effects of chronic ethanol exposure. Ultimately, these studies will provide insight into potential cellular mechanisms governing abuse and relapse in human alcoholics.

描述（由申请人提供）：当前申请的总体目标是了解有助于赋予病理行为（例如乙醇身体依赖后增强的负面影响）的神经生物学机制。最近的研究表明，内在外侧/基底外侧杏仁核（BLA）GABA能神经元严格控制。负面情绪的表达，包括慢性乙醇暴露后戒断期间表达的负面情绪，来自腹侧被盖/黑质致密部的多巴胺能输入已被证实。研究表明，乙醇依赖能够调节 GABA 能系统并抑制 BLA 主要神经元，而 BLA 主要神经元驱动焦虑样行为的表达。我们将通过利用成熟的慢性乙醇暴露大鼠模型并通过整合光遗传学、突触前和突触后多巴胺来测试我们的中心假设并实现我们的总体目标。 BLA 被广泛认为是神经回路的重要调节成分，控制着从长期乙醇暴露中戒断期间的焦虑样行为以及未接触过药物和特定暴露的动物的奖励寻求。目标 1 将通过检查乙醇依赖戒断期间的突触前多巴胺功能来测试我们的中心假设假设我们将通过将体外快速扫描循环伏安法与体外直接测量 DA 释放和再摄取结合起来。 DA 释放和长期乙醇暴露的光遗传学控制。根据我们之前的出版物，长期乙醇暴露将差异调节基础或“强直”DA 水平和阶段性 DA 释放，最终增强 DA 信号传导。使用体外全细胞膜片钳电生理学和创新的光遗传学方法来测量突触后 DA 受体信号传导，可以改变 BLA 中的 DA 受体功能。增加突触后 D1 和 D2 样 DA 受体信号传导，从而上调 DA 介导的 GABA 能功能抑制作用。具体目标 3 将通过整合光遗传学控制，将依赖 DA 信号传导的详细细胞效应置于整个动物环境中。我们的工作假设是，多巴胺神经传递和信号传导的依赖性相关变化最终控制了戒断依赖性焦虑样行为。高度集成的实验方法为控制长期乙醇暴露的负面强化效应的神经生物学机制提供了无与伦比的见解，最终，这些研究将提供对控制人类酗酒者滥用和复发的潜在细胞机制的见解。