HORMONE ACTIONS ON BEHAVIOR: CLINICAL NEUROPHARMACOLOGY

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。性腺神经类固醇是重要的行为调节剂，已被证明影响一系列临床上有意义的疾病，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组和非基因组机制调节经典神经递质功能来影响行为。到目前为止，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识别和功能神经成像方法来研究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效应)，以及这些效应的神经解剖学位置。这个基础科学项目将是第一个在相同的个体中应用这些方法来检查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之一。其中一系列研究将考察雌二醇对多巴胺能活动的影响。据推测，雌二醇将选择性地增强女性的多巴胺功能。第二系列研究将考察黄体酮的神经药理作用。有人假设孕酮及其代谢产物将通过调节多个受体位置，包括GABAα和NMDA，在男性和女性中产生直接的内感效应。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有价值的。这些研究将具有重要的应用意义，有助于未来开发针对性别的药物，这些药物在类固醇受体部位具有选择性作用，和/或与内源性神经类固醇联合作用。这些研究也有可能为开发和评估以类固醇为基础的药物提供信息并加强正在进行的努力。最后，这个项目将促进指导、发展和促进初级和早期职业同事在女性健康临床神经生物学方面的学术兴趣。

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.