BRAIN MONOAMINES AND LUTEINIZING HORMONE SECRETION

这项研究的总体目标是确定和表征中枢神经递质和神经肽系统对生理刺激的反应，这些神经递质和神经肽系统调节脑下垂体前叶分泌黄体生成素(LH)和催乳素(PRL)。在本资助期间进行的研究表明，NPY在哺乳中的作用之一是通过特异性地减少细胞外钙通过L型钙通道进入细胞内，从而放大DA对催乳素分泌的抑制作用。由于哺乳期也以明显的生理性吞噬为特征，而且NPY是摄食行为中最强大的中枢刺激剂，一组拟议的实验将检验这样一种假设，即弓状核的NPY神经元也参与了与哺乳期相关的过度吞噬。利用多种方法，本实验将研究中枢抗NPY免疫中和、反义寡核苷酸或NPY多肽拮抗剂对NPY传递的急性阻断是否会减少哺乳期间的摄食量，并将测试Y1和/或Y5受体是否介导了NPY在哺乳期的这一作用。第二个主要目标是确定在哺乳期负责上调下丘脑NPY的生理信号(S)。拟议的研究将检验与哺乳相关的低胰岛素血症增加下丘脑NPY表达的假设。这些研究将测试哺乳大鼠全身胰岛素治疗对下丘脑前NPY mRNA水平、NPY多肽浓度和NPY免疫反应性的影响，并将检查中断护理是否也改变了循环中的胰岛素浓度。为了测试瘦素是否也参与了弓状-脑室旁-背内侧下丘脑喂养网络中NPY的上调，第三组研究将评估中枢给药对哺乳期大鼠下丘脑前NPY原mRNA水平、NPY潮汐浓度和下丘脑NPY免疫反应性的影响。

The overall objective of this research program has been to identify and characterize the actions of the central neurotransmitter and neuropeptide systems that regulate the secretion of luteinizing hormone (LH) and prolactin (PRL) from the anterior pituitary gland in response to physiological stimuli. Studies conducted during the current funding period have demonstrated that one role of NPY in lactation is to amplify the inhibitory action of DA over PRL secretion, through a specific reduction in the entry of extracellular Ca2+ via L-type calcium channels. Because lactation is also characterized by a marked physiological hyperphagia, and because NPY is the most powerful central stimulant of feeding behavior, one set of proposed experiments will test the hypothesis that the NPY neurons of the arcuate nucleus also mediate the hyperphagia associated with lactation. Using a variety of approaches, the proposed experiments will investigate whether acute disruption of NPY transmission by central antiNPY immunoneutralization, antisense oligonucleotides or peptide antagonists of NPY decrease food intake during lactation and will test whether the Y1 and/or Y5 receptor mediates this action of NPY in lactation. A second major objective is to identify the physiological signal(s) responsible for the up-regulation of hypothalamic NPY during lactation. The proposed studies will test the hypothesis that the hypoinsulinemia associated with lactation increases the expression of NPY in the hypothalamus. These studies will test the effects of systemic insulin treatment of lactating rats on hypothalamic preproNPY mRNA levels, NPY peptide concentrations and NPY immunoreactivity, and will examine whether interruption of nursing, which reduces hypothalamic NPY expression, also alters circulating insulin concentrations. To test whether leptin might also be involved in the up-regulation of NPY in the arcuate-paraventricular-dorsomedial hypothalamic feeding network, a third set of studies will assess the effects of central leptin administration to lactating rats on hypothalamic pre proNPY mRNA levels, NPY tide concentrations and NPY immunoreactivity in the hypothalamus.