The proposed studies will test the hypothesis that high circulating prolactin (PRL) levels inhibit cyclic LH surges by an action on the brain. High PRL may inhibit LH surges by any of the following mechanisms. 1. Hyperprolactinemia could abolish the specific neurotransmitter signal(s) required for cyclic LH release. We will examine the pattern of turnover of changes in norepinephrine, dopamine and serotonin in discrete brain regions before and during LH surges. 2. Hyperprolactinemia could disrupt the rhythm of the """"""""biological clock"""""""" upon which all cyclic physiological functions, including LH surges, depend. We will examine the circadian rhythms in serotonin turnover, and Alpha- and Beta-adrenergic serotonergic receptors, particularly in the suprachiasmatic nucleus, because these are indices of the biological clock which may directly or indirectly affect LH release. 3. Hyperprolactinemia could affect LHRH-containing neurons to alter the amount and/or the kinetics of LHRH release. We will study LHRH release kinetics from synaptosomes prepared from the median eminence or from medial basal hypothalamic slices. The following methods will be used. A microdissection technique allows for the removal of discrete nuclei, fiber pathways and terminal projection fields from rat brain. We will estimate norepinephrine and dopamine turnover by measuring neurotransmitter concentrations before and after synthesis inhibition. Serotonin turnover will be estimated by assessment of 5-hydroxyindoleacetic acid/serotonin ratios and 5HT accumulation after inhibition of metabolism. High pressure liquid chromatography with electrochemical detection allows for quantitation of all of these compounds within samples from individual rats. Neurotransmitter receptors will be localized and quantitated using topical quantitative autoradiography. The ability of depolarizing stimuli to evoke LHRH release from median eminence synaptosomes or medial basal hypothalamic slices will be examined. The animal model to be used is the estadiol-treated ovariectomized rat. Our previous work demonstrates that elevated PRL can abolish cyclic LH release depending upon the estradiol treatment paradigm. This animal model allows us to investigate the direct neural effects of hyperprolactinemia on cyclic LH release in the absence of confounding ovarian effects.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD015955-05
Application #
3313340
Study Section
Biochemical Endocrinology Study Section (BCE)
Project Start
1982-06-01
Project End
1989-05-31
Budget Start
1987-06-01
Budget End
1988-05-31
Support Year
5
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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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