Dopaminergic Modulation of Excitatory Transmission in BNST and Regulation by Ethanol

BNST 中兴奋性传递的多巴胺能调节和乙醇的调节

• 批准号: 10264772
• 负责人: James Melchior
• 金额: $ 3.37万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10264772
• 关键词: Abstinence; Acute; Adaptive Behaviors; Adrenergic Receptor; Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Anxiety; Autoreceptors; Bathing; Behavior; Behavioral; Brain; Catecholamines; Cells; Characteristics; Chronic; Control Groups; Development; Dopamine; Dose; Electric Stimulation; Electrophysiology (science); Equilibrium; Ethanol; Event; Frequencies; Glutamates; Goals; Intoxication; Investigation; Measures; Mediating; Mediator of activation protein; Mental Depression; Modeling; Molecular; Mood Disorders; Motivation; Negative Reinforcements; Neuromodulator; Neurons; Norepinephrine; Optics; Output; Periodicity; Pharmaceutical Preparations; Pharmacology; Physiology; Positioning Attribute; Prevalence; Prevention; Progressive Disease; Receptor Activation; Regulation; Relapse; Rewards; Role; Scanning; Signal Transduction; Slice; Stress; Structure of terminal stria nuclei of preoptic region; Suggestion; Symptoms; Synapses; Synaptic Receptors; Synaptic Transmission; System; Techniques; Testing; Transgenic Mice; United States; Ventral Tegmental Area; Withdrawal; addiction; alcohol effect; alcohol exposure; alcohol seeking behavior; alcohol use disorder; anxiety states; anxiety-like behavior; behavioral response; beta-adrenergic receptor; dopaminergic neuron; economic cost; gamma-Aminobutyric Acid; insight; negative affect; nerve supply; neural circuit; noradrenergic; optogenetics; recruit; response; selective expression; stress state; stressor; synaptic function; temporal measurement; transmission process; uptake; vapor

Project Summary/Abstract Alcohol addiction is characterized by repeated relapses to alcohol abuse despite negative consequences. This counter-adaptive behavior is believed to result from adaptations in underlying neurocircuitry which occur in response to chronic alcohol abuse. These adaptations result in persistent negative affective states, during abstinence, which drive reinstatement of alcohol use as a means of negative reinforcement, or relief from negative conditions. The bed nucleus of the stria terminalis (BNST) is a key mediator of stress and anxiety states and behavioral responses to stressors. Models of stress-induced reinstatement of drug seeking have identified norepinephrine signaling in the BNST as critical to relapse behavior. Noradrenergic excitation of the BNST through β-adrenergic receptors promotes anxiety-like behaviors and drug reinstatement, whereas inhibition of BNST activity through α2-adrenergic receptors reduces anxiety-like behaviors. The BNST also receives prominent dopaminergic innervation from the ventral tegmental area (VTA). Investigations into the role of dopaminergic signaling in the BNST are relatively sparse and somewhat contradictory. For example, low doses of bath applied dopamine resulted in increased excitatory activity in the BNST, while high doses resulted in increased inhibitory actions. Further, the inhibitory actions are suggested to occur through dopamine cross-activation of α2-adrenergic receptors. In order to resolve these discrepancies, it is important to have a clear understanding of endogenous dopamine signals and how rapid changes in dopamine concentrations may selectively recruit post-synaptic receptor activation. Often, investigations of dopamine signaling use fast-scan cyclic voltammetry, which provides high temporal resolution of dopamine release and uptake in response to local electrical stimulation of terminals fields. However, in the BNST, dopamine and norepinephrine provide overlapping innervation, thus both catecholamines are released in response to local electrical stimulation, and cyclic voltammetry cannot distinguish between catecholamines. This hinders the use of this technique in assessing the potentially opposing roles of dopamine and norepinephrine signaling on BNST synaptic physiology. In this proposal we introduce a model in which we optogenetically target VTA dopamine neurons projecting to the BNST, such that we may use selective optical-stimulation of local dopamine release, measured with cyclic voltammetry, in BNST slices, ex vivo. Further, we propose to use optically-stimulated dopamine release in combination with whole cell electrophysiology to measure the cellular responses to endogenous dopamine signals. This ex vivo model allows us to employ various pharmacological manipulations to assess how dopamine signaling is integrated into synaptic physiology and to what degree endogenous dopamine signals recruit activation of α2-adrenergic receptors. Finally, we will examine how chronic intermittent ethanol vapor exposure alters the mechanisms of dopaminergic modulation of BNST synaptic function.

项目摘要/摘要 酒精成瘾的特征是对酒精滥用意图的重复继电器负面影响。这 据信，反自适应行为是由于在 对慢性酒精滥用的反应。这些适应导致持续的负面情感状态，期间 禁欲，这推动恢复酒精使用作为负强化的手段或缓解 负条件。 Stria末端（BNST）的床核us是压力和动画的关键中介者 国家和对压力源的行为反应。压力引起的恢复药物的模型具有 识别出BNST中的去甲肾上腺素信号对于中继行为至关重要。诺拉肾上腺素的兴奋 BNST通过β-肾上腺素能受体促进焦虑样行为和恢复药物，而 通过α2-肾上腺素受体抑制BNST活性会减少焦虑样行为。同时也是 从腹侧对接区域（VTA）接收突出的多巴胺能神经。调查 多巴胺能信号在BNST中的作用相对稀疏且有些矛盾。例如， 低剂量的沐浴多巴胺导致BNST的兴奋活动增加，而高剂量 导致抑制作用增加。此外，建议通过 α2-肾上腺素受体的多巴胺交叉激活。为了解决这些差异，这很重要 清楚地了解内源性多巴胺信号以及多巴胺的快速变化 浓度可以选择性地募集突触后受体激活。通常，多巴胺的调查 信号使用快速扫描循环伏安法，可提供多巴胺释放的高临时分辨率和 响应终端场的局部电气模拟的吸收。但是，在BNST，多巴胺和 去甲肾上腺素提供了重叠的神经，因此两个儿茶酚胺均根据局部释放 电刺激和环状伏安法无法区分儿茶酚胺。这阻碍了使用 该技术在评估多巴胺和去甲肾上腺素信号传导上的潜在相对作用方面 BNST合成生理学。在此提案中，我们介绍了一个模型，我们将其瞄准VTA。 投射到BNST的多巴胺神经元，因此我们可以使用局部的选择性光学刺激 多巴胺释放，用循环伏安法测量，在BNST片中，离体。此外，我们建议使用 光学刺激的多巴胺释放与全细胞电生理学结合使用，以测量细胞 对内源性多巴胺信号的反应。这种离体模型使我们能够采用各种药物 操纵以评估多巴胺信号如何整合到突触生理中 内源性多巴胺信号募集了α2-肾上腺素受体的激活。最后，我们将研究如何 慢性间歇性乙醇蒸气暴露改变了BNST多巴胺能调节的机制 突触功能。