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.

毒瘾是一个主要的健康问题，患者经常得不到治疗或治疗不足，从而导致复发。 压力是长期戒毒期间，大脑去甲肾上腺素水平升高的一个主要因素。 (NE) 参与适应不良的应激回路以促进 α2-肾上腺素受体 (α2-) 的激动作用。 ARs）可以抑制这种升高的 NE 音调，可乐定和胍法辛是临床前呈阳性的 α2 激动剂。 结果抑制了压力引起的药物寻求行为的恢复，但是最终的复发率。 我们勇敢地说，这是由于效果之间的竞争。 α2-AR 激动作用超出了其作为 NE 末端抑制性自身受体的常见作用。 研究这些对终纹床核（BNST）的影响，该床核是扩展的组成部分 在啮齿动物模型中，杏仁核参与依赖性大脑中压力和奖励的整合。 α2 激动剂的施用可减少应激诱导的恢复行为。在 BNST 中，α2-AR 激动剂。 可以抑制突触前末梢释放去甲肾上腺素和谷氨酸，后者是 最近，我们发现α2-AR 激动作用。 可以增强 BNST 的兴奋性，然而，这些效应背后的机制也是如此。 由于激活细胞的具体识别是关键的未知数，因此该提案旨在确定。 α2-AR激动剂诱导BNST神经元谷氨酸能传递增强的机制 及其与电路活动的相关性，并通过了解该规定来开始确定该规定的影响 我们勇敢地说，突触后 α2A-AR 的激活会增强兴奋性。 为了验证这一假设，我们通过抑制 HCN 通道对 BNST 神经元群体做出反应。 结合电生理学研究，旨在揭示胍法辛激活机制 通过解剖学研究来确定 BNST 内的影响，旨在识别胍法辛激活的群体 通过这些实验，我们希望更好地理解 BNST 神经元的非典型效应。 α2-AR 激动作用和 BNST 活性的增强这样做，我们将能够研究行为。 和这种特定的胍法辛效应的电路相关性，并为靶向治疗最大限度地发挥作用打开了大门 其临床疗效。