CENTRAL CONTROL OF OXYTOCIN RELEASE DURING GESTATION

该项目的总体目标是识别和表征控制催产素（OT）分泌的中枢神经递质系统，催产素在分娩和哺乳期间被释放到体循环和室旁核（PVN）和视上核（SON）核内（即核内释放）。在分娩、哺乳期和妊娠后期，核内释放的OT对正常的、反射性的OT系统激活至关重要。我们已经确定了三种兴奋性神经递质系统，去甲肾上腺素（NE）、组胺（HA）和谷氨酸（GLU），它们相互作用并增加泌乳期间全身和核内OT的释放。此外，妊娠相关卵巢激素的变化增加了妊娠后期的OT mRNA。然而，这些兴奋性神经递质系统和卵巢激素的作用，以及妊娠后期OT刺激的重要性尚不清楚。本申请中提出的实验将测试一个整体假设，即妊娠后期OT系统的激活是由于NE、HA和GLU的刺激作用造成的，这是卵巢激素环境变化（雌二醇升高，黄体酮下降）的结果，而此时OT系统的激活对于随后在分娩和哺乳期间正常反射性释放OT是必要的。具体目的是：1)确定兴奋性递质系统（NE， HA， GLU）在妊娠后期全身和核内OT释放中的作用。2)通过卵巢激素的作用来检测妊娠后期是否发生OT激活，并确定这些激素对兴奋性神经递质系统的影响。3)检测在妊娠后期预防OT激活是否会干扰分娩和哺乳期OT的全身和核内释放。这些研究将使用体内微透析来评估中枢神经化学物质的释放，并在妊娠和有意识的大鼠激素治疗期间局部给药大细胞核。这些研究将有助于本计划的总体目标，通过确定；1)妊娠期间激活OT系统的神经递质；2)妊娠相关卵巢激素对OT释放的贡献；3)妊娠期间OT释放对分娩和哺乳期间发生的反射性释放的重要性。

The overall objective of this project is to identify and characterize central neurotransmitter systems that control secretion of oxytocin (OT), which is released into the systemic circulation and within the paraventricular (PVN) and supruoptic (SON) nuclei (i.e. intranuclear release) during parturition and lactation. The intranuclear release of OT is critical for normal, reflexive activation of the OT system during parturition, lactation, and late gestation. We have identified three excitatory neurotransmitter systems, norepinephrine (NE), histamine (HA), and glutamate (GLU) that interact and increase systemic and intranuclear OT release during lactation. Furthermore, changes in pregnancy-associated ovarian hormones increase OT mRNA in late pregnancy. However, the contributions of these excitatory neurotransmitter systems and ovarian hormones, as well as the importance of OT stimulation during late gestation are unknown. The experiments proposed in this application will test the overall hypothesis that activation of the OT system during late gestation results from stimulatory actions of NE, HA and GLU, as a result of the changing ovarian hormonal milieu (rise in estradiol, fall in progesterone), and that activation of the OT system at this time is necessary for the normal, reflexive release of OT subsequently during parturition and lactation. The Specific Aims are: 1) To determine the roles of excitatory transmitter systems (NE, HA, GLU) in systemic and intranuclear OT release in late gestation. 2) To test whether OT activation in late gestation occurs through actions of the ovarian hormones, and determine effects of these hormones on excitatory neurotransmitter systems. 3) To test whether prevention of OT activation in late gestation disrupts systemic and intranuclear release of OT during parturition and lactation. These studies will use in vivo microdialysis to evaluate central neurochemical release, and to administer pharmacological agents locally to magnocellular nuclei during gestation and during hormone treatment in conscious rats. These studies will contribute to the overall objectives of this program by identifying the; 1) neurotransmitters activating the OT system during pregnancy, 2) the contributions of gestation-associated ovarian hormones to OT release, and 3) importance of OT release during gestation to reflexive release which occurs during parturition and lactation.