CENTRAL CONTROL OF OXYTOCIN RELEASE DURING GESTATION

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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.