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

吸毒成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，导致复发。 压力是复发的主要前驱因素。在长期戒酒期间，大脑去甲肾上腺素水平升高 (Ne)使用适应不良的压力回路，以促进恢复。α2-肾上腺素能受体激动剂(α2- ARS)可以抑制这种升高的NE音调。可乐定和胍法辛是临床前阳性的α-2激动剂 结果抑制应激诱导的寻药行为恢复。然而，最终的复发率 这种治疗方法对人类的影响不大。我们假设这是由于各种影响之间的竞争。 α2-AR激动剂的作用超出了其在NE终末上作为抑制性自身受体的通常被引用的作用。我们的目标是 研究这些效应在终纹床核(BNST)中的作用，BNST是延展的 杏仁核与依赖脑中应激和奖励的整合有关。在啮齿动物模型中，直接 给予α-2激动剂可减少应激诱导的恢复行为。在BNST，α-2-AR激动剂 可以抑制去甲肾上腺素和谷氨酸从突触前终末释放，后者是一种 臂旁核(PBN)传入神经元的特异性效应。最近，我们发现α-2-AR激动剂 可增强BNST的兴奋性。然而，这些效应背后的机制也 作为被激活细胞的具体标识，都是关键的未知数。这项提案旨在确定 α_2-AR激动剂增强BNST神经元谷氨酸能传递的机制 以及它与电路活动的相关性，并通过理解 调节的细胞数量。我们假设突触后α2A-Ars的激活增强了兴奋性 一组BNST神经元通过抑制HCN通道的反应。为了检验这一假设，我们 建议结合电生理学研究，旨在揭示鸟嘌呤激活的机制 在BNST内的作用，通过解剖学研究，目的是确定鸟嘌呤激活的群体 BNST神经元。通过这些实验，我们希望能更好地理解非正则效应 α-2-AR激动剂和BNST活性增强。通过这样做，我们将能够研究行为 与电路的这种特定的金刚烷效应相关，并为靶向治疗打开大门，以最大限度地提高 其临床疗效。

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.