Regulation of Prolactin Secretion at the Lactotroph

描述(申请人提供)：本次更新申请的中心假设是，在生理条件下，催乳素(PRL)的分泌受到多巴胺(DA)的抑制和催产素(OT)的刺激，这些神经元的活动受到下丘脑更高水平的输入和PRL本身的调节。我们将通过一种新的跨学科的实验和数学方法来检验这一假说，以达到以下特定目的：(1)确定DA、OT和PRL分泌之间的生理相互作用的基础；(2)确定发情周期阶段乳汁对OT的PRL释放特性反应差异的生理基础；(3)表征OT对垂体催乳素的作用机制；(4)表征DA和其他PRL释放调节剂对OT诱导的乳汁反应的关系。这些目标意义重大，因为它们将挑战公认的教条，即在生理环境中，催乳素的分泌只受下丘脑DA的抑制控制。 公共卫生相关性：目前临床上操纵催乳素分泌的方法包括操纵多巴胺。例如，良性高分泌的垂体瘤称为催乳素瘤，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，对患者的福利有严重影响。事实上，正如我们的初步数据显示的那样，如果催乳素的分泌也受催产素等肽能释放因子的控制，那么这可能是治疗催乳素分泌障碍的另一种方法。此外，催乳素被认为与其300多种其他生物学行为有关。这些研究的结果可能会成为治疗这些疾病的一种方法。

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.