DEHYDROEPIANDROSTERONE--A NEUROSTEROID MODULATING AGGRES

去氢雄甾酮——一种神经类固醇调节剂

• 批准号: 6528529
• 负责人: NEAL G SIMON
• 金额: $ 20.07万
• 依托单位: LEHIGH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-10 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6528529
• 关键词: GABA receptor; aggression; allosteric site; androgen inhibitor; androgen receptor; behavioral /social science research tag; benzodiazepine receptor; chloride channels; dehydroepiandrosterone; gamma aminobutyrate; inhibitor /antagonist; laboratory mouse; neuroendocrine system; neuropharmacology; ovariectomy; pregnenolone; psychopharmacology; receptor binding

Neurosteroids, which are synthesized in the brains of humans and other mammals, are under investigation for use in a range of human health conditions (e.g., anxiety, memory, immune function, problems associated with aging). One of these compounds, dehydroepiandrosterone (DHEA), is a powerful inhibitor of aggression in murine models when given for fifteen days and potentially may be useful in the management of inappropriate human aggression. Although the biosynthesis and metabolism of DHEA have been described, a significant gap exists concerning the mechanism(s) of this anti-aggressive effect. We know that 15 days of DHEA treatment reduces whole brain levels of pregnenolone sulfate (PREG-S), a GABAA receptor antagonist that works directly at the membrane level, and we recently discovered that DHEA also up-regulates androgen receptor (AR) in the limbic system, demonstrating a genomic effect. Both events can contribute to enhanced GABA activity, an inhibitory neurotransmitter known to reduce aggression. The major goal of the proposed research, therefore, will be to identify and/or quantitate the metabolic, membrane level, and genomic effects of extended DHEA treatment and then determine the contributions of each to the aggression- inhibiting effect of this neurosteroid. Experiments will be undertaken to localize the specific brain regions where DHEA treatment causes a significant decline in PREG-S, characterize the regional changes in GABAA receptor binding that occur over the course of DHEA exposure, define effects of the androgenic metabolites of DHEA on AR regulation that may be linked to the anti-aggressive action of this neurosteroid and, finally, perform functional biobehavioral and in vivo microinfusion studies involving pharmacological manipulations to begin defining underlying neural regulatory mechanisms. The results should achieve two objectives. One is that critical mechanisms and sites of action for the inhibition of aggression by DHEA will be defined, advancing models of the neurobiology of this behavior. The other is that with the characterization of both membrane-level and genomic actions linked to the anti- aggressive effect of DHEA, a "cross-talk" cellular signaling system associated with extended neurosteroid treatment would be established. This finding would significantly advance our understanding of the mechanism of action of DHEA, an important consideration given proposed clinical uses.

神经类固醇是在人类和其他哺乳动物的大脑中合成的，目前正在研究用于治疗一系列人类健康状况（例如焦虑、记忆、免疫功能、与衰老相关的问题）。 其中一种化合物，脱氢表雄酮 (DHEA)，在小鼠模型中给予十五天后，是一种强大的攻击性抑制剂，并且可能有助于控制人类不适当的攻击性。 尽管 DHEA 的生物合成和代谢已被描述，但关于这种抗攻击作用的机制仍存在显着的空白。 我们知道，15 天的 DHEA 治疗会降低全脑孕烯醇酮硫酸盐 (PREG-S) 的水平，这是一种直接在膜水平发挥作用的 GABAA 受体拮抗剂，而且我们最近发现 DHEA 还能上调边缘系统中的雄激素受体 (AR)，这证明了基因组效应。 这两种事件都有助于增强 GABA 活性，GABA 是一种抑制性神经递质，可以减少攻击性。 因此，拟议研究的主要目标是确定和/或定量延长 DHEA 治疗的代谢、膜水平和基因组效应，然后确定每种效应对这种神经类固醇的攻击性抑制作用的贡献。 将进行实验来定位 DHEA 治疗导致 PREG-S 显着下降的特定大脑区域，表征在 DHEA 暴露过程中发生的 GABAA 受体结合的区域变化，确定 DHEA 雄激素代谢物对 AR 调节的影响，这可能与这种神经类固醇的抗攻击作用有关，最后，进行功能性生物行为和体内实验 微输注研究涉及药理学操作，以开始定义潜在的神经调节机制。结果应该实现两个目标。 一是将定义 DHEA 抑制攻击行为的关键机制和作用位点，从而推进这种行为的神经生物学模型。 另一个是，通过与 DHEA 的抗侵袭作用相关的膜水平和基因组作用的表征，将建立与延长神经类固醇治疗相关的“串扰”细胞信号系统。 这一发现将显着增进我们对 DHEA 作用机制的理解，这是考虑到拟议的临床用途的一个重要考虑因素。