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，目前正在研究用于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)，在给药15天后，在小鼠模型中是一种强大的攻击抑制剂，可能对管理不适当的人类攻击行为有用。虽然DHEA的生物合成和代谢已经被描述，但关于这种抗攻击作用的机制(S)，仍然存在着重大的空白。我们知道，15天的脱氢表雄酮治疗降低了全脑硫酸孕烯醇酮(PREG-S)的水平，这是一种直接在膜水平起作用的GAAA受体拮抗剂，我们最近发现，脱氢表雄酮还上调了边缘系统中的雄激素受体(AR)，显示了一种基因组效应。这两种事件都有助于增强GABA的活性，GABA是一种已知的减少攻击性的抑制性神经递质。因此，这项拟议研究的主要目标将是确定和/或量化延长DHEA治疗的代谢、膜水平和基因组效应，然后确定它们对这种神经类固醇的攻击抑制效应的贡献。将进行实验，以定位脱氢表雄酮治疗导致PREG-S显著下降的特定大脑区域，表征在脱氢表雄酮暴露过程中发生的GABA受体结合的区域变化，确定脱氢表雄酮的雄激素代谢物对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，进行涉及药物操纵的功能性生物行为和体内微输注研究，以开始确定潜在的神经调节机制。结果应该达到两个目标。其一是将定义DHEA抑制攻击的关键机制和作用部位，推进这一行为的神经生物学模型。另一种观点是，通过对与DHEA的抗侵袭作用相关的膜水平和基因组作用的研究，将建立一个与延长神经类固醇治疗相关的“串扰”细胞信号系统。这一发现将极大地促进我们对DHEA作用机制的理解，考虑到拟议的临床用途，这是一个重要的考虑因素。

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.