EXCITATORY AMINO ACIDS: ROLE IN GNRH, LH & FSH SECRETION

过去五年的重大进展表明， 兴奋性氨基酸递质（EAAs）在神经系统中起着重要作用。 控制GnRH神经分泌。更新建议的重点是阐明 EAA调节GnRH分泌的机制，以及进一步 描述神经内分泌信号的顺序/相互作用， 诱导排卵前LH峰。目标1将决定 一氧化氮（NO）作为EAA效应的下游介质， 下丘脑控制GnRH和LH分泌。EAA对 将评估下丘脑NO的产生， 一氧化氮的产生是否受类固醇的调节， 发情前期LH峰的时间。目标2将确定阿片神经元是否 具有通过以下途径紧张性抑制下丘脑谷氨酸和/或NO神经元的功能 检测纳洛酮对下丘脑谷氨酸释放和NO的影响 生产目标3将确定精确的第二信使系统 利用谷氨酸和NO调节GnRH和LH释放。下丘脑 第二信使、鸟苷酸环化酶和环氧合酶的表达， 将在周期和排卵前LH峰期间测定， 在施用谷氨酸盐和/或NO剂之后。酶抑制剂 也将用于确定这些系统的功能意义。 目标4将确定谷氨酸神经信号传导的缺陷是否是 参与生殖老化，通过确定是否EAA受体，EAA 释放速率和NO的产生在下丘脑中减弱， 中年大鼠在发情前期的下午。目标5将确定 血红素氧合酶在大脑中合成一氧化碳， 在LH峰产生中的生理作用，并由 谷氨酸盐和/或类固醇。目标6将确定类固醇激素是否 控制下丘脑谷氨酸转运蛋白表达作为一种机制， 调节突触的谷氨酸水平。这些研究将加强我们的 了解控制GnRH的复杂神经内分泌机制， LH分泌在女性。

Significant progress within the last 5 years has established that excitatory amino acid transmitters (EAAs) play a central role in the control of GnRH neurosecretion. The renewal proposal focuses on elucidating the mechanisms utilized by EAAs to regulate GnRH secretion, and further delineating the sequence/interaction of neuroendocrine signals in the induction of the preovulatory LH surge. Aim 1 will determine the role of nitric oxide (NO) as a downstream mediator of EAA effects in the hypothalamus to control GnRH and LH secretion. The effect of EAAs on hypothalamic NO production will be evaluated as will the essential question of whether NO production is regulated by steroids and is elevated at the time of the proestrus LH surge. Aim 2 will determine whether opioid neurons function to tonically inhibit hypothalamic glutamate and/or NO neurons by examining the effect of naloxone on hypothalamic glutamate release and NO production. Aim 3 will determine the precise second messenger systems utilized by glutamate and NO to regulate GnRH and LH release. Hypothalamic expression of the second messenger, guanylate cyclase and cyclooxygenase, will be determined during the cycle and the preovulatory LH surge, and following administration of glutamate and/or NO agents. Enzyme inhibitors will also be used to determine functional significance of these systems. Aim 4 will determine whether a defect in glutamate neurosignaling is involved in reproductive aging by determining whether EAA receptors, EAA release rates and NO production are attenuated in the hypothalamus of the middle-aged rat on proestrus afternoon. Aim 5 will establish whether the enzyme heme oxygenase, which synthesizes carbon monoxide in the brain, has a physiological role in production of the LH surge and is regulated by glutamate and/or steroids. Aim 6 will establish whether steroid hormones control hypothalamic glutamate transporter expression as a mechanism of regulating glutamate levels at the synapse. These studies will enhance our understanding of the complex neuroendocrine mechanisms controlling GnRH and LH secretion in the female.