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 酒精成瘾的特点是反复酗酒，尽管有负面后果。这 反适应行为被认为是由于潜在神经回路的适应导致的，这种适应发生在 对长期酗酒的反应。这些适应导致持续的负面情感状态，在 禁欲，促使恢复酒精使用，作为一种负面强化的手段，或缓解 消极的条件。终纹床核(BNST)是压力和焦虑的关键介质 应激源的状态和行为反应。应激诱导的药物寻求恢复模型有 发现BNST中的去甲肾上腺素信号对复发行为至关重要。去甲肾上腺素的兴奋作用 BNST通过β-肾上腺素能受体促进焦虑样行为和药物恢复，而 通过α2-肾上腺素能受体抑制BNST活性可减少焦虑样行为。英国国民警卫队还 从腹侧被盖区(VTA)接受显著的多巴胺能神经支配。对该事件的调查 多巴胺能信号在BNST中的作用相对较少且有一定的矛盾性。例如, 低剂量的BASH应用多巴胺可增加BNST的兴奋性，而高剂量的BASH可使BNST的兴奋性增强 导致抑制作用增强。此外，建议抑制作用通过以下途径发生 多巴胺交叉激活α2-肾上腺素能受体。为了解决这些差异，重要的是 清楚了解内源性多巴胺信号以及多巴胺的快速变化 药物浓度可能选择性地激活突触后受体。通常，对多巴胺的研究 信号使用快速扫描循环伏安法，它提供了高时间分辨率的多巴胺释放和 对终端野局部电刺激的反应摄取。然而，在BNST中，多巴胺和 去甲肾上腺素提供重叠的神经支配，因此两种儿茶酚胺都被释放，以响应局部 电刺激和循环伏安法不能区分儿茶酚胺。这阻碍了它的使用 这项技术在评估多巴胺和去甲肾上腺素信号转导的潜在对立作用中的作用 BNST突触生理学。在这项建议中，我们引入了一个模型，在该模型中，我们以VTA为目标进行光遗传 向BNST投射的多巴胺神经元，以便我们可以使用选择性光刺激局部 用循环伏安法测定体外培养的BNST切片中的多巴胺释放。此外，我们建议使用 光刺激多巴胺释放结合全细胞电生理学测量细胞 对内源性多巴胺信号的反应。这种体外模型允许我们利用各种药理作用 评估多巴胺信号如何整合到突触生理中以及整合到何种程度的操作 内源性多巴胺信号征募α2-肾上腺素能受体的激活。最后，我们将研究如何 慢性间歇性乙醇蒸气暴露改变BNST的多巴胺能调节机制 突触功能。