Neurosteroids foster sedation by engaging tonic GABAA-Rs within the mesopontine tegmental anesthesia area (MPTA)

IF 2.5 4区 医学 Q3 NEUROSCIENCES
Mark Baron , Marshall Devor
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引用次数: 0

Abstract

Neurosteroids are endogenous molecules with anxiolytic, anticonvulsant, sleep-promoting and sedative effects. They are biosynthesized de novo within the brain, among other tissues, and are thought to act primarily as positive allosteric modulators of high-affinity extrasynaptic GABAAδ-receptors. The location of action of neurosteroids in the brain, however, remains unknown. We have demonstrated that GABAergic anesthetics act within the brainstem mesopontine tegmental anesthesia area (MPTA) to induce and maintain anesthetic loss-of-consciousness. Here we asked whether endogenous and synthetic neurosteroids might also act in the MPTA to induce their suppressive effects. Direct exposure of the MPTA to the endogenous neurosteroids pregnenolone and progesterone, their metabolites testosterone, allopregnanolone and 3α5α-THDOC, and the synthetic neurosteroids ganaxolone and alphaxalone, was found to be pro-anesthetic. Although we cannot rule out additional sites of action, results of this study suggest that the suppressive effects of neurosteroids are due, at least in part, to actions within the MPTA, presumably by recruitment of dedicated neuronal circuitry. This undermines the usual presumption that neurosteroids, like other sedatives, endogenous somnogens and anesthetics, act by nonspecific global distribution.
神经类固醇通过激活中脑被盖麻醉区(MPTA)内的强直 GABAA-Rs,促进镇静。
神经类固醇是具有抗焦虑、抗惊厥、促进睡眠和镇静作用的内源性分子。它们在大脑和其他组织中从头开始生物合成,被认为主要作为高亲和性突触外 GABAAδ 受体的正异构调节剂发挥作用。然而,神经类固醇在大脑中的作用位置仍然未知。我们已经证明,GABA能麻醉剂作用于脑干中脑被盖麻醉区(MPTA),诱导并维持麻醉后的意识丧失。在此,我们提出了一个问题:内源性和合成的神经类固醇是否也会在 MPTA 中发挥作用,诱导其抑制作用。我们发现,MPTA 直接暴露于内源性神经类固醇孕烯诺酮和孕酮、其代谢产物睾酮、异孕烯诺酮和 3α5α-THDOC 以及合成神经类固醇甘珀酸和阿法沙龙中会产生麻醉促进作用。虽然我们不能排除其他作用部位,但本研究结果表明,神经类固醇的抑制作用至少部分是由于 MPTA 内的作用,可能是通过招募专用神经元回路产生的。这推翻了通常的推测,即神经类固醇与其他镇静剂、内源性体液素和麻醉剂一样,通过非特异性的全球分布发挥作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Neuroscience Letters
Neuroscience Letters 医学-神经科学
CiteScore
5.20
自引率
0.00%
发文量
408
审稿时长
50 days
期刊介绍: Neuroscience Letters is devoted to the rapid publication of short, high-quality papers of interest to the broad community of neuroscientists. Only papers which will make a significant addition to the literature in the field will be published. Papers in all areas of neuroscience - molecular, cellular, developmental, systems, behavioral and cognitive, as well as computational - will be considered for publication. Submission of laboratory investigations that shed light on disease mechanisms is encouraged. Special Issues, edited by Guest Editors to cover new and rapidly-moving areas, will include invited mini-reviews. Occasional mini-reviews in especially timely areas will be considered for publication, without invitation, outside of Special Issues; these un-solicited mini-reviews can be submitted without invitation but must be of very high quality. Clinical studies will also be published if they provide new information about organization or actions of the nervous system, or provide new insights into the neurobiology of disease. NSL does not publish case reports.
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