BRAIN MONOAMINES AND LUTEINIZING HORMONE SECRETION

本研究计划的总体目标是确定和表征中枢神经递质和神经肽系统的作用，这些系统调节垂体前叶对生理刺激的促黄体生成素（LH）和催乳素（PRL）分泌。 在当前资助期间进行的研究表明，NPY在哺乳期的一个作用是通过特异性减少细胞外Ca 2+通过L型钙通道的进入，放大DA对PRL分泌的抑制作用。 因为哺乳期也具有明显的生理性摄食过多的特征，并且因为NPY是摄食行为的最强有力的中枢刺激物，所以一组拟议的实验将检验弓状核的NPY神经元也介导与哺乳期相关的摄食过多的假设。 使用各种方法，拟议的实验将调查是否急性中断的NPY传输中枢antiNPY免疫中和，反义寡核苷酸或肽拮抗剂的NPY减少哺乳期的食物摄入量，并将测试是否Y1和/或Y 5受体介导的这种行动的NPY在哺乳期。 第二个主要目的是确定哺乳期间下丘脑NPY上调的生理信号。 拟议的研究将测试这一假设，即与哺乳相关的低胰岛素血症增加下丘脑中NPY的表达。 这些研究将测试哺乳期大鼠全身胰岛素治疗对下丘脑前神经肽Y原mRNA水平、神经肽Y肽浓度和神经肽Y免疫反应性的影响，并将检查减少下丘脑神经肽Y表达的哺乳中断是否也改变循环胰岛素浓度。 为了测试瘦素是否也可能参与下丘脑腹侧-室旁-背内侧摄食网络中NPY的上调，第三组研究将评估中枢瘦素给药对哺乳大鼠下丘脑前体前体NPY原mRNA水平、下丘脑中NPY潮汐浓度和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.