CATECHOLAMINES AND REPRODUCTIVE AGING

我们建议确定与年龄相关的改变在 儿茶酚胺和内源性阿片肽神经元 生殖系统的启动和维持 大鼠的衰老。我们还将评估与年龄相关的 衰老过程中激素分泌的变化 脑多巴胺能神经元。拟议中的实验将 利用幼年(3至4个月大)、性成熟的大鼠； 老年(11-15个月大)正常骑车或 处于持续发情(CE)状态；和老年(24-25个月大)CE 长埃文斯品系的老鼠。我们将在治疗期间评估黄体生成素脉冲 测定中年大鼠发情前黄体生成素峰值 促黄体生成素分泌动力学的成分刚刚改变 到CE状态的开始。我们将进行类似的评估 促黄体生成素排卵前高峰时的搏动性促黄体生成素 可乐定或溴隐亭反复诱发CE大鼠模型 假孕大鼠。这些研究将利用频繁(每5次 最小)未麻醉和未麻醉的大鼠的血液样本 没有压力。血清雌二醇(E_2)和雌二醇(E_2)慢性升高的作用 催乳素(PRL)与增龄性多巴胺(DA)下降 将对神经功能进行评估。剂量和时间- E_2和E_2影响的依赖性和区域特异性 测定脑多巴胺能神经元的催乳素水平。另外，时间- 催乳素刺激下多巴胺能神经元从雌二醇恢复的过程 将会被确定。我们最近记录了慢性病 阿片受体的刺激导致脑电活动显著增加。 睾酮对黄体生成素分泌的负反馈作用 雌二醇的负反馈效应和正反馈效应 女性。我们将评估EOP神经元系统在 男性负反馈敏感度随年龄增长而增加。 这些研究将利用长期接触麻醉剂 拮抗剂纳洛酮，缓释微丸。类似 研究将在老年CE中使用慢性吗啡治疗 大鼠和随后对由此产生的变化的测定 雌二醇对黄体生成素释放的影响最后，我们观察到一个 类固醇诱导的阿片受体下调参与了 产生促黄体生成素的一系列神经元事件 涌动。因此，我们将评估与年龄相关的假设 排卵前黄体生成素高峰的消失是一种 这种阿片类神经机制的缺陷。总而言之，这些 研究将促进我们对神经元和荷尔蒙的了解 参与启动和持续的机制 生殖衰老。

We propose to determine the role of age-related alterations in catecholamine (CA) and endogenous opioid peptide (EOP) neuronal systems in the initiation and maintenance of reproductive senescence in rats. We will also evaluate the role of age-related alterations in hormone secretion in the process of the aging of brain dopaminergic neurons. The proposed experiments will utilize young (3 to 4 months old), sexually mature rats; middle- aged (11-15 months old) rats which are either normally cycling or in the constant estrous (CE) state; and old (24-25 months old) CE rats of the Long Evans strain. We will evaluate LH pulses during the proestrous LH surge in middle-aged rats to determine the components of LH secretory dynamics which are altered just prior to the onset of the CE state. We will conduct similar evaluations of pulsatile LH release during the preovulatory surge of LH induced by clonidine in CE rats or by bromocriptine in repeatedly pseudopregnant rats. These studies will utilize frequent (every 5 min.) blood sampling of rats which are unanesthetized and unstressed. The role of chronic elevations in serum (E2) and prolactin (PRL) in the age-related decline in dopamine (DA) neuronal function will be evaluated. The dose-and time- dependency and the regional specificity of the effects of E2 and PRL on brain DA neurons would be determined. Also, the time- course of the recovery of DA neurons from the E2 on PRL insult will be determined. We have documented recently that chronic stimulation of opiate receptors cause a marked increase in the negative feedback effects of testosterone on LH secretion in males and in the negative and positive feedback effects of E2 in females. We would evaluate the role of EOP neuronal systems in the age-related increase in negative feedback sensitivity in males. These studies will utilize chronic exposure to the narcotic antagonist, naloxone, by a sustained-release pellet. Similar studies will be done using chronic morphine treatment in old CE rats and subsequent determination of the resulting changes in the effects of E2 on LH release. Finally, we have observed that a steroid-induced down-regulation of opioid receptors is involved in the series of neuronal events which generate the proestrous LH surge. Thus, we will evaluate the hypothesis that the age-related extinction of the preovulatory LH surge is a consequence of a deficit in this opioid-neuronal mechanism. Collectively, these studies will advance our knowledge of the neuronal and hormonal mechanism involved in the initiation and persistence of reproductive senescence.