This project addresses the fundamental issue of whether excitatory amino acids (EAAs), such as glutamic acid or aspartic acid, are involved in the neuroendocrine regulation of gonadotropin secretion in the female rat. While significant work has been done in the male on this question, surprisingly little work has been performed in the female. Gaining a better understanding of the neuroendocrine events and mechanisms which regulate the gonadotropin surge in the female is important, since it could lead to new ways to regulate reproduction and to new methods for treating infertility. The proposed study will determine the ability of EAAs to regulate GnRH, gonadotropin and prolactin secretion in the female rat using both in vitro and in vivo approaches. In vitro studies will examine the ability of a variety of natural (endogenous) and synthetic EAAs to regulate GnRH release from hypothalami of estrogen-primed ovariectomized (ovx.) adult rats perfused in vitro. The specific receptor mediating each EAA effect will also be determined as will the ability of each EAA to repetitively stimulate GnRH release. EAAs will also be administered in vivo to validate that the effects observed in vitro are real effects that can be observed in the natural in vivo environment. Aim 2 will examine whether EAA effect is influenced by gonadal steroid background. Ovx. rats with and without estradiol or estradiol plus progesterone replacement will be used in this aim. Both in vitro GnRH release and in vivo LH, FSH and PRL release after EAA administration will be assessed in these animals. In Aim 3, specific NMDA and non-NMDA receptor antagonists will be employed in ovx. estrogen-progesterone treated animals, and during the different days of the cycle to determine the physiological role of EAAs in negative and positive feedback regulation. Furthermore, the role of endogenous EAAs in pulsatile GnRH and LH release in the female will also be examined. Aim 4 will determine if the effect of EAAs on GnRH, LH, FSH and prolactin release is mediated through effects on other neurotransmitter systems (catecholamine, acetylcholine and NPY) known to regulate the release of these hormones and releasing hormones. Specific antagonists to each respective system mentioned above will be utilized in vitro and in vivo to answer this question. Also, the possibility that these neurotransmitter systems could use EAAs to mediate their effect on GnRH, gonadotropin or PRL release will be examined. Aim 5 will examine whether steroids can modulate EAA receptor density and affinity in neuroendocrine tissues such as the hypothalamus using ovx. rats with and without steroid replacement, as well as cycling rats on each day of the cycle. These studies will provide important new information on the precise role of EAAs in the regulation GnRH, gonadotropin and prolactin secretion in the female.
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