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: 9189454
• 负责人: Nicholas Andrew Harris
• 金额: $ 2.82万
• 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 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9189454
• 关键词: ADRA2A gene; Abstinence; Adrenergic Agonists; Adrenergic Receptor; Aftercare; Agonist; Alcohols; Amygdaloid structure; Area; Autoreceptors; Behavior; Behavioral; Brain; Cells; Chronic; Clinical; Clinical Trials; Clonidine; Corticotropin-Releasing Hormone; Cyclic AMP; Cyclic Nucleotides; Data; Disease; Drug Addiction; Electrophysiology (science); FOS gene; Failure; Fluorescent in Situ Hybridization; Future; Glutamates; Guanfacine; HCN1 gene; Health; Human; Injection of therapeutic agent; 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; inhibitor/antagonist; knock-down; neuronal excitability; novel; parabrachial nucleus; postsynaptic; pre-clinical; preclinical trial; receptor; research study; 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。患者往往得不到治疗或治疗不足，导致复发。 压力是复吸的主要前因。在长期禁欲期间，大脑去甲肾上腺素水平升高 (NE)利用适应不良的压力回路来促进恢复。α2-肾上腺素能受体（α2- AR）可以抑制这种升高的NE音调。可乐定和胍法辛是α2-受体激动剂，临床前 结果抑制了压力诱导的寻求药物行为的恢复。然而，最终的复发率 在人类中，这种治疗没有改变。我们假设这是由于效应之间的竞争 α2-AR激动作用超出了其通常作为NE末端抑制性自身受体的作用。我们的目标是 研究终纹床核（BNST）中的这些效应，BNST是延伸的 杏仁核参与了依赖性大脑中压力和奖励的整合。在啮齿动物模型中，直接 α2激动剂的给药减少了应激诱导的恢复行为。在BNST中，α2-AR激动 可以抑制突触前末梢释放去甲肾上腺素和谷氨酸，后者是一种 对臂旁核（PBN）传入的特异性作用。最近，我们发现α2-AR激动 可使BNST兴奋性增强。然而，这些效应背后的机制，以及 作为激活细胞的具体识别，是关键的未知数。本建议旨在确定 α2-AR激动剂增强BNST神经元的多巴胺能传递的机制 及其与电路活动的相关性，并开始了解 调节细胞的数量。我们假设突触后α2A-ARs的激活增强了兴奋性突触后膜的兴奋性。 通过抑制HCN通道在BNST神经元群体中的反应。为了验证这个假设，我们 建议联合收割机电生理研究，旨在揭示胍法辛激活 BNST内的作用，解剖学研究旨在确定胍法辛激活的 BNST神经元。通过这些实验，我们希望能对非正则效应有更好的理解 α2-AR激动和增强BNST的活性。这样一来，我们就能够研究 和电路相关性，这种特定的胍法辛效应，并打开大门，有针对性的治疗，以最大限度地 其临床疗效。