The longterm objective of this research is to evaluate the neuroendocrine mechanisms by which hyperprolactinemia (hyperPRL) suppresses female reproductive function.
The specific aims of this proposal are to test the working hypothesis that hyperPRL suppresses pulsatile and cyclic LH release by modulating opiatergic neuronal activity. We will assess whether this, in turn, influences the activity of catecholamine- containing neurons resulting in an altered pattern of GnRH release or whether opiates directly affect GnRH neurons. Furthermore, we will test two corollary hypotheses: (1) when hyperPRL does not affect LH, it is because the opiatergic/catecholamine/GnRH link is not functional in that endocrine milieu; and (b) if we restore the opiatergic/catecholamine/GnRH pattern, we can restore normal LH secretion, despite the presence of hyperPRL. Finally, we will test the hypothesis that hyperPRL compromises pituitary responsiveness. To test these hypotheses, we will (1) differentiate the circumstances under which hyperPRL does and does not suppress LH release; (2) examine how hyperPRL alters opioid neuronal tone; (3) assess whether hyperPRL- induced changes in opiate and catecholamine activity determine the efficacy of hyperPRL to suppress LH; and (4) determine whether hyperPRL decreases pituitary responsiveness to GnRH. We will assess opiate tone using 4 indices of activity: quantitation of opiate peptide concentrations in microdissected brain regions, monitoring of patterns of opiate peptide release into microdialysis probes placed in critical brain regions, measurement of opiate mRNA expression assessed using in situ hybridization, and autoradiographic quantitation of opiate receptor densities in key terminal areas. Three indices of catecholamine activity will be autoradiographic quantitation of adrenergic receptor densities. Patterns of GnRH release will be measured at the pituitary gland using dialysis methodology. Pituitary responsiveness will be measured in vivo and in vitro using the reverse hemolytic plaque assay in combination with in situ hybridization. Using this multifaceted approach, we should deepen the understanding of the neuroendocrine factors that regulate the pulsatile and cyclic release of LH and how hyperPRL perturbs this balance resulting in a different pattern of LH secretion.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
7R01HD015955-11
Application #
2197255
Study Section
Reproductive Endocrinology Study Section (REN)
Project Start
1982-06-01
Project End
1995-03-31
Budget Start
1993-04-01
Budget End
1995-03-31
Support Year
11
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Physiology
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
Sagrillo, C A; Grattan, D R; McCarthy, M M et al. (1996) Hormonal and neurotransmitter regulation of GnRH gene expression and related reproductive behaviors. Behav Genet 26:241-77
Ottinger, M A; Rosewell, K L; Weiland, N G et al. (1995) Effect of lactation on hypothalamic preproenkephalin gene expression. J Neuroendocrinol 7:341-6
McShane, T M; Wise, P M; Jennes, L (1994) Neuropeptide-Y neurons projectioning to the medial septum-diagonal band do not have access to fenestrated capillaries in the rat brain. Mol Cell Neurosci 5:459-65
Chiu, S; Wise, P M (1994) Prolactin receptor mRNA localization in the hypothalamus by in situ hybridization. J Neuroendocrinol 6:191-9
Wise, P M (1994) Nathan Shock Memorial Lecture 1991. Changing neuroendocrine function during aging: impact on diurnal and pulsatile rhythms. Exp Gerontol 29:13-9
Wise, P M; Weiland, N G; Scarbrough, K et al. (1994) Changing diurnal and pulsatile rhythms during aging. Neurobiol Aging 15:503-7
Larson, G H; Wise, P M (1994) Constitutive and regulated prolactin secretion: effects of estradiol. Biol Reprod 50:357-62
Scarbrough, K; Jakubowski, M; Levin, N et al. (1994) The effect of time of day on levels of hypothalamic proopiomelanocortin primary transcript, processing intermediate and messenger ribonucleic acid in proestrous and estrous rats. Endocrinology 134:555-61
Wise, P M (1993) Neuroendocrine ageing: its impact on the reproductive system of the female rat. J Reprod Fertil Suppl 46:35-46
Wise, P M; Scarbrough, K; Larson, G et al. (1993) Assessment of gene expression and peptide secretion from individual cells. Microsc Res Tech 25:40-5

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