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

• 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
• 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

 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（由应用程序提供）：当前应用的总体目标是了解神经生物学机制，这些机制有助于会议病理行为，例如乙醇物理依赖性后增强的负面影响。最近的研究表明，固有的侧向/基底外侧杏仁核（BLA）GABA能神经元紧紧控制了阴性情绪的表达，包括慢性乙醇暴露后戒断期间表达的情绪。已证明来自腹侧对接/黑质nigra pars compacta的多巴胺能输入可调节这种GABA能系统，并抑制BLA主神经元，这些神经元可驱动动画样行为的表达。基于强有力的初步证据，我们提出的实验将检验中心假设，即乙醇依赖性通过对这些GABA能神经元的多巴胺能调节失调而抑制了BLA输出。我们将通过利用良好的慢性乙醇暴露大鼠模型以及整合光遗传学，前和突触后多巴胺神经生理学以及行为实验方法来检验中心假设并实现总体目标。 BLA已广泛地成为神经元回路的重要调节成分，该组件控制着从慢性乙醇暴露中撤出期间的焦虑样行为以及在药物和暴露动物中寻求奖励。具体目标1将通过检查从乙醇依赖性退出期间检查突触前多巴胺功能来检验我们的中心假设假设。我们将通过将体外快速扫描环状伏安法与DA释放和慢性乙醇暴露的光遗传学控制进行整合，直接在体外测量DA释放和重新摄取。我们假设，基于我们以前的出版物，慢性乙醇暴露会不同地调节基本或“补品” DA级别和阶段性DA释放，以最终增强DA信号传导。特定的目标2将使用创新的光遗传学方法来测量突触后DA受体信号传导的创新光遗传学方法，研究BLA中突触后DA受体功能如何改变BLA。我们的工作假设是，乙醇的物理依赖性将增加突触后D1和D2样的DA接收器信号传导，从而使DA介导的GABA能功能的抑制被上调。特定的目标3将通过将DA释放的光遗传控制与BLA依赖性行为的体内测量相结合，将依赖对DA信号依赖的详细细胞效应在整个动物上下文中。我们的工作假设是，多巴胺神经传递和信号传达的依赖相关的变化最终控制了戒断依赖性焦虑样行为。拟议的工作员工是一种独特且高度综合的实验方法，可提供对慢性乙醇暴露的负面增强作用的神经生物学机制的无与伦比的见解。最终，这些研究将洞悉有关人类酗酒者滥用和缓解的潜在细胞机制。