HORMONE ACTIONS ON BEHAVIOR: CLINICAL NEUROPHARMACOLOGY

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。性腺神经类固醇是重要的行为调节剂，已被证明对一系列临床显著状况有影响，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全动物行为模型的数据表明，性腺神经类固醇通过各种基因和非基因组机制直接调节神经元活动以及调节经典神经递质功能来影响行为。迄今为止，雌激素和黄体酮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鉴别和功能性神经影像学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体中应用这些方法来检查雌激素和黄体酮调节人类临床神经递质功能的方式和解剖位置的项目。一系列的研究将检验雌二醇对多巴胺能活性的影响。据推测，雌二醇会选择性地增强女性多巴胺的功能。第二个系列的研究将检验黄体酮的神经药理作用。据推测，黄体酮及其代谢物会通过调节多种受体位点，包括GABA α和NMDA，在男性和女性中产生直接的内感受作用。这些信息对于扩大我们对情绪和行为调节中性别差异的神经生物学基础的理解将是无价的。这些研究将在帮助未来开发针对性别的药物方面具有重要的应用意义，这些药物在甾体受体位点具有选择性作用和/或适合与内源性神经类固醇联合使用。这些研究也有可能为正在进行的开发和评估类固醇药物的努力提供信息和加强。最后，本项目将促进指导、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.