CENTRAL CONTROL OF OXYTOCIN RELEASE DURING GESTATION

该项目的总体目标是确定和表征控制催产素(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、室旁核(PVN)和视上核(SON)内(即核内释放)。在分娩、哺乳和妊娠晚期，催产素的核内释放对催产素系统的正常、反射性激活至关重要。我们已经确定了三个兴奋性神经递质系统，去甲肾上腺素(NE)、组胺(HA)和谷氨酸(GLU)，它们在哺乳期相互作用并增加全身和核内OT的释放。此外，妊娠相关卵巢激素的变化增加了妊娠晚期OTmRNA的表达。然而，这些兴奋性神经递质系统和卵巢激素的作用以及催产素刺激在妊娠晚期的重要性尚不清楚。本申请中提出的实验将检验这样一个总体假设，即妊娠后期OT系统的激活是NE、HA和GLU刺激作用的结果，这是卵巢激素环境变化(雌二醇上升，孕酮下降)的结果，此时OT系统的激活对于随后的分娩和哺乳期间OT的正常、反射性释放是必要的。其具体目的是：1)确定兴奋性递质系统(NE、HA、GLU)在妊娠晚期全身性和核内OT释放中的作用。2)检测妊娠晚期OT的激活是否通过卵巢激素的作用而发生，以及这些激素对兴奋性神经递质系统的影响。3)检测在妊娠晚期阻止OT的激活是否干扰分娩和哺乳期间的全身和核内OT的释放。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，并在妊娠期间和清醒大鼠的激素治疗期间将药物局部应用于大鼠的巨细胞核。这些研究将通过确定：1)孕期激活催产素系统的神经递质，2)妊娠相关卵巢激素对催产素释放的贡献，以及3)孕期催产素释放对分娩和哺乳期反射性催产素释放的重要性，从而有助于该计划的总体目标。

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.