NEUROCHEMICAL CONTROL OF OXYTOCIN RELEASE

描述(改编自申请人的摘要)：总体情况 本研究项目的目标是确定和表征 调节脑神经递质分泌的神经递质的作用 神经垂体中的催产素，尤其是那些 参与多肽释放的神经化学系统 对哺乳期哺乳的反应。拟议的研究将 去甲肾上腺素(NE)释放的总体假设的检验方面 在下丘脑内，大细胞核与突触后相互作用 与神经肽Y(NPY)共同释放，可能是一种多肽能协同释放。 递质，带有兴奋性氨基酸，最有可能是谷氨酸(Glu) 作用于AMPA受体亚型，并具有抑制性GABA能 系统，以产生典型的阵发性OT激活 哺乳期的分泌物。我们还获得了证据表明，在 哺乳期的早期，由哺乳提供的传入刺激 子代参与OT mRNA表达的上调，在 部分是通过增加大细胞核内OT的局部释放。 第一个特定的目标使用电刺激的组合， 神经药理学和体内微透析测试方法 无论是通过特定方式激活或中断传播 脑干去甲肾上腺素能细胞群改变中枢释放 去甲肾上腺素和全身释放催产素作为对哺乳的反应。第二 具体目的是进一步研究NE、NPY、Glu之间的相互作用 和GABA对OT分泌的调控作用。研究将测试AMPA是否 受体控制大细胞核中NE或NPY的释放，并 GABA系统是否调节OT对兴奋性的分泌反应 投入。全细胞电生理记录将从 免疫组织化学染色显示视上脑片中的OT神经元 去甲肾上腺素和去甲肾上腺素的作用及相互作用 谷氨酸对OT神经元活性的影响。第三个具体目标将进一步 下丘脑OT基因的神经内分泌调节研究 在哺乳期的表现。将使用原位杂交技术 确定与哺乳有关的生理刺激是否 改变OT神经元离散亚群中的OT mRNA。为了进一步研究 集中释放的OT参与OT mRNA的表达，研究将 测试集中应用催产素是否增加下丘脑催产素基因表达 在非哺乳期大鼠中，将使用微量注射方法来 确定OT提高OT mRNA水平的神经作用部位。 对去甲肾上腺素和谷氨酸受体拮抗剂的研究将测试OT mRNA 大细胞核中的水平受去甲肾上腺素-谷氨酸的调节 互动就像OT发布一样。

DESCRIPTION (Adapted from the applicant's abstract): The overall objective of this research project is to identify and characterize the actions of brain neurotransmitters that regulate the secretion of oxytocin (OT) from the neurohypophysis, and especially, those neurochemical systems that are involved in the release of the peptide in response to suckling during lactation. The proposed research will test aspects of the overall hypothesis that norepinephrine (NE) released within the hypothalamic magnocellular nuclei interacts post-synaptically with neuropeptide Y (NPY), which may be co- released as a peptidergic co- transmitter, with an excitatory amino acid, most likely glutamate (Glu) acting at an AMPA receptor subtype, and with inhibitory GABAergic systems, to produce the characteristic episodic activation of OT secretion during lactation. We have also obtained evidence that during the early stages of lactation, afferent stimuli provided by the suckling offspring participate in the up-regulation of OT mRNA expression, in part by increasing the local release of OT in the magnocellular nuclei. The first Specific Aim uses a combination of electrical stimulation, neuropharmacological, and in vivo microdialysis approaches to test whether activation or disruption of transmission through specific noradrenergic cell groups of the brain stem alters the central release of NE and systemic release of OT in response to suckling. The second Specific Aim is to further examine the interactions among NE, NPY, Glu and GABA in control of OT secretion. Studies will test whether AMPA receptors control NE or NPY release in the magnocellular nuclei and whether GABA systems modulate the OT secretory response to excitatory inputs. Whole-cell electrophysiological recordings will be made from immunohistochemically identified OT neurons in slices of the supraoptic nucleus in vitro to examine the effects and interactions between NE and Glu on activity of OT neurons. The third Specific Aim will further investigate the neuroendocrine regulation of hypothalamic OT mRNA expression in lactation. In situ hybridization will be used to determine whether the physiological stimuli associated with suckling alter OT mRNA in discrete subsets of OT neurons. To further examine the involvement of centrally released OT in OT mRNA expression, studies will test whether centrally applied OT increases hypothalamic OT mRNA levels in non-lactating rats, and microinjection approaches will be used to determine the neural site of action of OT in increasing OT mRNA levels. Studies with NE and GLu receptor antagonists will test whether OT mRNA levels in the magnocellular nuclei are regulated by a noradrenergic-Glu interaction as is OT release.