HORMONE ACTIONS ON BEHAVIOR: CLINICAL NEUROPHARMACOLOGY

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。性腺神经类固醇是重要的行为调节剂，并已被证明影响一系列临床显著的条件，包括性行为，睡眠，认知，药物和酒精滥用，情感障碍，疼痛敏感性，癫痫发作障碍和应激反应。最近的分子和细胞研究以及来自整个动物行为模型的数据表明，性腺神经类固醇通过直接调节神经元活动以及通过各种基因和非基因机制调节经典神经递质功能来影响行为。迄今为止，雌激素和孕激素对人类神经递质功能的影响几乎没有受到关注。我们和其他人已经成功地使用药物辨别和功能性神经成像方法来检查精神活性药物改变经典神经递质功能的方式（即，药物的临床神经药理学作用）以及这些作用的神经解剖学位置。这个基础科学项目将是第一个在同一个人中应用这些方法来研究雌激素和孕激素调节人类临床神经递质功能的方式和解剖位置的项目。一系列的研究将检查雌二醇对多巴胺能活性的影响。据推测，雌二醇将增强多巴胺功能选择性的妇女。第二系列研究将检查孕酮的神经药理学作用。据推测，孕酮及其代谢产物将通过调节男性和女性的多个受体位点（包括GABA α和NMDA）产生直接的内感受性效应。这些信息对于扩大我们对情绪和行为调节性别差异的神经生物学基础的理解将是非常宝贵的。这些研究将具有重要的应用意义，在帮助未来的性别特异性药物的发展具有选择性的作用，在类固醇受体网站和/或定制的工作与内源性神经类固醇组合。这些研究也可能为开发和评估类固醇药物提供信息并加强正在进行的努力。最后，该项目将促进指导，发展和促进我们的初级和早期职业同事在妇女健康的临床神经生物学的学术兴趣。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Gonadal neurosteroids are important modulators of behavior and have been shown to impact a range of clinically significant conditions, including sexual behavior, sleep, cognition, drug and alcohol abuse, affective disorders, pain sensitivity, epileptic seizure disorders and stress reactivity. Recent molecular and cellular studies as well as data from whole animal behavioral models indicate that gonadal neurosteroids influence behavior through the direct regulation of neuronal activity, as well as the modulation of classical neurotransmitter function, through a variety of both genonic and nongenomic mechanisms. To date, the effects of estrogen and progesterone on neurotransmitter function in humans have received almost no attention. We, and others, have successfully used drug discrimination and functional neuroimaging methodologies to examine the manner in which psychoactive drugs alter classical neurotransmitter function (i.e., clinical neuropharmacological effects of drugs), as well as the neuroanatomical locations of these effects. This basic science project will be among the first to apply these methodologies within the same individuals to examine the manner and anatomical locations in which estrogen and progesterone modulate clinical neurotransmitter function in humans. One series of studies will examine the effects of estradiol on dopaminergic activity. It is hypothesized that estradiol will enhance dopamine function selectively in women. A second series of studies will examine the neuropharmacological effects of progesterone. It is hypothesized that progesterone and its metabolites will engender direct interoceptive effects via modulation of multiple receptor sites, including GABA alpha and NMDA, in both men and women. This information will be invaluable for expanding our understanding of the neurobiological basis of gender differences in mood and behavior regulation. These studies will have important applied significance in helping future development of gender-specific medications having selective effects at steroidal receptor sites and/or tailored to work in combination with endogenous neurosteroids. It is also likely that these studies will inform and enhance ongoing efforts to develop and evaluate steroid-based medications. Finally, this project will promote the mentoring, development and promotion of our junior and early career colleagues' academic interests in the clinical neurobiology of women's health.