DHEA--A NEUROSTEROID MODULATING AGGRESSION

神经类固醇是在人类和其他哺乳动物的大脑中合成的，目前正在研究将其用于一系列人类健康状况（例如，焦虑、记忆、免疫功能、与衰老有关的问题）。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抑制剂，并且可能对管理不适当的人类攻击有用。虽然DHEA的生物合成和代谢已经被描述，但关于这种抗侵袭作用的机制存在显著的空白。我们知道15天的DHEA治疗可以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起作用的GABAA受体拮抗剂，我们最近发现DHEA还可以上调边缘系统中的雄激素受体（AR），显示出基因组效应。这两种情况都有助于增强GABA活性，这是一种抑制性神经递质，可以减少攻击性。因此，本研究的主要目标是确定和/或量化脱氢表雄酮长期治疗的代谢、膜水平和基因组效应，然后确定每个因素对这种神经类固醇的攻击抑制作用的贡献。实验将定位DHEA治疗导致PREG-S显著下降的特定大脑区域，描述DHEA暴露过程中GABAA受体结合的区域变化，确定DHEA的雄激素代谢物对AR调节的影响，这可能与这种神经类固醇的抗侵袭作用有关，最后，进行功能性生物行为和体内微输注研究，包括药理学操作，开始定义潜在的神经调节机制。结果应该达到两个目标。一个是DHEA抑制攻击的关键机制和作用位点将被定义，推进这种行为的神经生物学模型。另一方面，随着与DHEA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。这一发现将大大提高我们对脱氢表雄酮的作用机制的理解，这是提出临床应用的一个重要考虑。

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.