NEUROCHEMICAL CONTROL OF OXYTOCIN RELEASE

描述（改编自申请人的摘要）：总体 该研究项目的目的是确定和表征 大脑神经递质的作用，调节分泌 催产素（OT）从神经垂体，特别是，那些 参与肽释放的神经化学系统 在哺乳期对吮吸的反应。拟议的研究将 去甲肾上腺素（NE）释放的总体假设的测试方面 下丘脑大细胞核内突触后相互作用 与神经肽Y（NPY），这可能是共同释放的肽能共- 递质，带有兴奋性氨基酸，最可能是谷氨酸（Glu） 作用于AMPA受体亚型，并具有抑制性GABA能 系统，以产生OT的特征性情景激活 哺乳期的分泌物。我们还获得证据表明， 哺乳的早期阶段，哺乳动物提供的传入刺激 后代参与OT mRNA表达的上调， 部分通过增加大细胞核中OT的局部释放。 第一个特定目标使用电刺激的组合， 神经药理学和体内微透析方法来测试 无论是激活还是破坏通过特定的 脑干的去甲肾上腺素能细胞群改变中枢神经系统的释放 的NE和全身释放的OT在响应吮吸。 第二 具体目的是进一步研究NE、NPY、Glu之间的相互作用 和GABA控制OT分泌。研究将测试AMPA是否 受体控制NE或NPY在大细胞核中的释放， GABA系统是否调节OT分泌反应， 输入。全细胞电生理记录将从 在视上神经切片中化学鉴定OT神经元 核在体外检查NE和 Glu对OT神经元活性的影响。第三个具体目标将进一步 探讨下丘脑OT mRNA的神经内分泌调节 在哺乳期的表达。原位杂交将用于 确定与哺乳相关的生理刺激是否 改变OT神经元的离散子集中的OT mRNA。进一步审查 研究表明，中枢释放的OT参与OT mRNA的表达， 测试中枢应用OT是否增加下丘脑OT mRNA水平 在非哺乳期大鼠中，显微注射方法将用于 确定OT在增加OT mRNA水平中的神经作用部位。 NE和GLu受体拮抗剂的研究将测试OT mRNA 大细胞核中的水平由去甲肾上腺素能-Glu调节， 像OT释放一样的互动。

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.