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.
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.
|Corthell, J T; Stathopoulos, A M; Watson, C C et al. (2013) Olfactory bulb monoamine concentrations vary with time of day. Neuroscience 247:234-41|
|Helena, Cleyde V; Cristancho-Gordo, Ruth; Gonzalez-Iglesias, Arturo E et al. (2011) Systemic oxytocin induces a prolactin secretory rhythm via the pelvic nerve in ovariectomized rats. Am J Physiol Regul Integr Comp Physiol 301:R676-81|
|Watts, Margaret; Tabak, Joel; Bertram, Richard (2011) Mathematical modeling demonstrates how multiple slow processes can provide adjustable control of islet bursting. Islets 3:320-6|
|Tabak, Joel; Tomaiuolo, Maurizio; Gonzalez-Iglesias, Arturo E et al. (2011) Fast-activating voltage- and calcium-dependent potassium (BK) conductance promotes bursting in pituitary cells: a dynamic clamp study. J Neurosci 31:16855-63|
|Teka, Wondimu; Tabak, Joel; Vo, Theodore et al. (2011) The Dynamics Underlying Pseudo-Plateau Bursting in a Pituitary Cell Model. J Math Neurosci 1:|
|Sirzen-Zelenskaya, A; Gonzalez-Iglesias, A E; Boutet de Monvel, J et al. (2011) Prolactin induces a hyperpolarising current in rat paraventricular oxytocinergic neurones. J Neuroendocrinol 23:883-93|
|Tomaiuolo, M; Bertram, R; Gonzalez-Iglesias, A E et al. (2010) Investigating heterogeneity of intracellular calcium dynamics in anterior pituitary lactotrophs using a combined modelling/experimental approach. J Neuroendocrinol 22:1279-89|
|Bertram, R; Helena, C V; Gonzalez-Iglesias, A E et al. (2010) A tale of two rhythms: the emerging roles of oxytocin in rhythmic prolactin release. J Neuroendocrinol 22:778-84|
|Kennett, Jessica E; Poletini, Maristela O; Fitch, Cheryl A et al. (2009) Antagonism of oxytocin prevents suckling- and estradiol-induced, but not progesterone-induced, secretion of prolactin. Endocrinology 150:2292-9|
|Helena, Cleyde V; McKee, De'Nise T; Bertram, Richard et al. (2009) The rhythmic secretion of mating-induced prolactin secretion is controlled by prolactin acting centrally. Endocrinology 150:3245-51|
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