Non-canonical activating effects of alpha2a adrenergic receptor agonism in the bed nucleus of the stria terminalis

终纹床核中 α2a 肾上腺素能受体激动的非典型激活作用

• 批准号: 9757748
• 负责人: Nicholas Andrew Harris
• 金额: $ 4.24万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-05-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9757748
• 关键词: ADRA2A gene; Abstinence; Adrenergic Agonists; Adrenergic Receptor; Aftercare; Agonist; Alcohols; Amygdaloid structure; Anatomy; Area; Autoreceptors; Behavior; Behavioral; Brain; Cells; Chronic; Clinical; Clinical Trials; Clonidine; Concentration Camps; Corticotropin-Releasing Hormone; Cyclic Nucleotides; Data; Disease; Drug Addiction; Electrophysiology (science); FOS gene; Failure; Fluorescent in Situ Hybridization; Future; Glutamates; Guanfacine; HCN1 gene; Health; Human; Injections; Kinetics; Knock-out; Maps; Messenger RNA; Methods; Molecular; Mus; Neurons; Neurotransmitters; Norepinephrine; Patients; Pharmaceutical Preparations; Population; Presynaptic Terminals; Protein Isoforms; Regulation; Relapse; Reporting; Rewards; Rodent Model; Role; Saline; Stress; Structure of terminal stria nuclei of preoptic region; Synapses; System; Testing; Transcript; Transgenic Mice; United States; Viral; Withdrawal; addiction; affective disturbance; alpha 2 agonist; anxiety states; base; behavioral study; clinical efficacy; craving; cyclic nucleotide-gated cation channel; cyclic-nucleotide gated ion channels; drug of abuse; drug seeking behavior; effective therapy; experimental study; inhibitor/antagonist; knock-down; neuronal excitability; novel; parabrachial nucleus; postsynaptic; pre-clinical; preclinical trial; receptor; response; small hairpin RNA; study population; targeted treatment; transmission process

Drug addiction is a major health concern. Patients often go untreated or undertreated, leading to relapse. Stress is a major antecedent of relapse. During protracted abstinence, elevated levels of brain norepinephrine (NE) engage maladaptive stress circuitry to promote reinstatement. Agonism at α2-adrenergic receptors (α2- ARs) can dampen this elevated NE tone. Clonidine and guanfacine are α2-agonists with positive preclinical results dampening stress-induced reinstatement of drug seeking behavior. However, ultimate rates of relapse in humans are unchanged by this treatment. We hypothesize that this is due to competition among the effects of α2-AR agonism beyond its commonly cited role as an inhibitory autoreceptor on NE terminals. We aim to investigate these effects in the bed nucleus of the stria terminalis (BNST), a component of the extended amygdala implicated in the integration of stress and reward in the dependent brain. In rodent models, direct administration of α2 agonists reduces stress-induced reinstatement behaviors. In the BNST, α2-AR agonism can inhibit release of both norepinephrine and glutamate from presynaptic terminals, with the latter being a specific effect on afferents from the parabrachial nucleus (PBN). Recently, we have found that α2-AR agonism can produce enhancement of excitability in BNST. However, the mechanism underlying these effects, as well as the specific identification of the cells activated, are critical unknowns. This proposal aims to determine the mechanism underlying α2-AR agonism-induced enhancement of glutamatergic transmission in BNST neurons and its relevance to circuit activity, and to begin to determine the impact of this regulation by understanding the population of cells regulated. We hypothesize that activation of postsynaptic α2A-ARs enhances excitatory responses in a population of BNST neurons through inhibition of HCN channels. To test this hypothesis, we propose to combine electrophysiological studies aimed at uncovering the mechanism of guanfacine activating effects within the BNST with anatomical studies aimed at identifying the guanfacine-activated population of BNST neurons. Through these experiments, we hope to gain a better understanding of non-canonical effects of α2-AR agonism and enhancement of activity in the BNST. In doing so, we will be able to study the behavioral and circuit relevance of this specific guanfacine effect and open the door for targeted therapeutics to maximize its clinical efficacy.

吸毒成瘾是一个主要的健康问题。患者经常没有治疗或没有治疗，导致退休。 压力是退休的主要先例。在持久的节制期间，脑去甲肾上腺素水平升高 （NE）参与不良适应应力回路以促进恢复原状。 α2-肾上腺素受体的激动剂（α2- ARS）可以该死这种高架的NE语气。可乐定和鸟宁是α2激动剂，具有阳性临床前 结果导致应力引起的恢复药物寻求行为。但是，最终退休率 在人类中，这种治疗方法不变。我们假设这是由于效果之间的竞争 α2-ar激动剂超出其通常在NE末端作为抑制性自身受体的作用。我们的目标 研究这些效果在质末端（BNST）的床核中，该效果是扩展的组成部分 杏仁核在依赖大脑中的压力和奖励的整合中实施。在啮齿动物模型中，直接 α2激动剂的给药减少了应力诱导的恢复行为。在BNST中，α2-ar激动剂 可以抑制从突触前末端释放去甲肾上腺素和谷氨酸，后者是 对副核（PBN）的传入对传入的特异性影响。最近，我们发现α2-ar激动剂 可以在BNST中产生兴奋的增强。但是，这些效果的基础机制也 由于激活的细胞的特定鉴定是关键的未知数。该建议旨在确定 BNST神经元中谷氨酸能传播的α2-AR激动剂诱导的基础机制 及其与电路活动的相关性，并开始通过理解该法规的影响 细胞的种群受调节。我们假设突触后α2A-AR的激活增强了兴奋性 通过抑制HCN通道，BNST神经元人群中的反应。为了检验这一假设，我们 提案结合旨在发现圭素激活机制的电生理研究 BNST内的影响，旨在确定鸟量激活的人群 BNST神经元。通过这些实验，我们希望能更好地了解非规范效应 BNST中的α2-ar激动剂和活性的增强。这样，我们将能够研究行为 和这种特定鸟丝效应的电路相关性，并为有针对性的治疗打开了大门以最大化 它的临床效率。