Regulation of Prolactin Secretion at the Lactotroph

描述（由申请人提供）：本更新申请的中心假设是，在生理条件下，催乳素（PRL）分泌受多巴胺（DA）抑制，受催产素（OT）刺激，这些神经元的活动受更高的下丘脑输入和PRL本身调节。我们将用一种新的跨学科实验和数学方法来测试这一假设，以实现以下具体目标：（1）确定DA、OT和PRL分泌之间生理相互作用的基础，（2）确定催乳素对OT的PRL释放特性的反应的动情周期阶段差异的生理基础，（3）探讨OT对垂体催乳细胞的作用机制;（4）探讨DA和其它催乳素释放调节剂对OT诱导的催乳细胞反应的影响。这些目标是重要的，因为它们将挑战公认的教条，即在生理环境中PRL分泌仅受下丘脑DA的抑制控制。 公共卫生相关性：目前控制催乳素分泌的临床方法涉及多巴胺的控制。例如，良性分泌过多的垂体瘤被称为催乳素瘤，用多巴胺激动剂溴隐亭或卡麦角林治疗。这些药物中的每一种都有副作用，对病人的福利有严重的影响。事实上，正如我们的初步数据表明，如果催乳素分泌也受到肽能释放因子如催产素的控制，那么这可能是治疗催乳素分泌障碍的另一种方法。此外，催乳素还与300多种其他生物学作用相关的疾病有关。这些研究的结果可以作为治疗这些疾病的方法。

DESCRIPTION (provided by applicant): The Central Hypothesis of this renewal application is that under physiological conditions, prolactin (PRL) secretion is inhibited by dopamine (DA) and stimulated by oxytocin (OT) and that the activities of these neurons are regulated by higher hypothalamic input and PRL itself. We will test this hypothesis with a novel interdisciplinary experimental and mathematical approach to the following specific aims: (1) To determine the basis for a physiological interaction between DA, OT and PRL secretion, (2) To determine the physiological basis for the estrous cycle stage differences in the response of lactotropes to the PRL-releasing properties of OT, (3) To characterize the mechanism of action of OT on pituitary lactotropes and (4) To characterize the relationship of DA and other modulators of PRL release on OT-induced responses in lactotropes. These aims are significant because they will challenge accepted dogma that PRL secretion in physiological circumstances is only under inhibitory control of hypothalamic DA. PUBLIC HEALTH RELEVANCE: Current clinical approaches to manipulating prolactin secretion involve manipulation of dopamine. For example, the benign hypersecreting pituitary tumor known as a prolactinoma is treated with the dopamine agonists bromocryptine or cabergoline. Each of these drugs has side effects which have serious implications for patients' welfare. Indeed, as our preliminary data suggest, if prolactin secretion is also under the control of peptidergic releasing factors such as oxytocin, then this may be another approach to treating disorders of prolactin secretion. Moreover, prolactin has been implicated in disorders related to more than 300 of its other biological actions. Results from these studies may serve as an approach to treating these disorders.