The longterm objective of this research program is to determine the neuroendocrine mechanisms regulating LH and prolactin (PRL) secretion in mammals. Proposed studies examine hypothalamic mechanisms by which hyperprolactinemia (HP) and testosterone (T) may inhibit tonic LE secretion in male rats. This problem is of central importance in the control of mammalian fertility and has profound contraceptive significance. We will utilize an acute, reversible hyperprolactinemia model where there is a dose-related, transitory suppression of the postcastration rise in LH levels produced by ovine PRL (oPRL) administration. This animal model allows us to investigate the direct brain and pituitary effects of hyperprolactinemia on tonic LH release in the absence of confounding gonadal influences. We will analyze the effects of selected, increasing doses of administered oPRL on the frequency and amplitude of pulsatile LH secretion. Norepinephrine (NE), epinephrine, dopamine and GABA synthesis and turnover rate constants will be determined in intact, castrated, castrated-PRL-treated and castrated-T-treated rats, in microdissected brain regions which are likely sites of synapse of these neurons on LH-RH neurons. Quantitative in situ hybridization histochemistry will be utilized to determine whether PRL and T affect single cell levels of glutamic acid decarboxylase mRNA in medial preoptic area (MPoA) GABAergic neurons. Whether HP inhibits median eminence LH-RH turnover estimated by a new colchicine method, or blocks the LH response to third ventricular NE, MPOA infused bicuculline or iv N-methyl-D-aspartate will be ascertained. In this reversible model, brain parameters will be determined before (Oh),' during (48h) and after (96h) PRL suppression of the postcastration LH rise, thus assessing which endpoints change at a time of maximal suppression (48h) and whether these changes reverse or others appear at a time of reversal (96h). This research will further our understanding of the hypothalamic mechanisms regulating LH and PRL secretion and the ways in which elevated circulating PRL levels and feedback steroid affect these mechanisms.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Biochemical Endocrinology Study Section (BCE)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Maryland Baltimore
Schools of Medicine
United States
Zip Code
Joh, Hung-Dong; Searles, Robin V; Selmanoff, Michael et al. (2006) Estradiol alters only GAD67 mRNA levels in ischemic rat brain with no consequent effects on GABA. J Cereb Blood Flow Metab 26:518-26
Yoo, M J; Searles, R V; He, J R et al. (2000) Castration rapidly decreases hypothalamic gamma-aminobutyric acidergic neuronal activity in both male and female rats. Brain Res 878:10-Jan
Searles, R V; Yoo, M J; He, J R et al. (2000) Sex differences in GABA turnover and glutamic acid decarboxylase (GAD(65) and GAD(67)) mRNA in the rat hypothalamus. Brain Res 878:9-Nov
Grattan, D R; Selmanoff, M (1997) Sex differences in the activity of gamma-aminobutyric acidergic neurons in the rat hypothalamus. Brain Res 775:244-9
Grattan, D R; Rocca, M S; Strauss, K I et al. (1996) GABAergic neuronal activity and mRNA levels for both forms of glutamic acid decarboxylase (GAD65 and GAD67) are reduced in the diagonal band of Broca during the afternoon of proestrus. Brain Res 733:46-55
Grattan, D R; Rocca, M S; Sagrillo, C A et al. (1996) Antiandrogen microimplants into the rostral medial preoptic area decrease gamma-aminobutyric acidergic neuronal activity and increase luteinizing hormone secretion in the intact male rat. Endocrinology 137:4167-73
Park, S K; Strouse, D A; Selmanoff, M (1996) Prolactin- and testosterone-induced inhibition of LH secretion after orchidectomy: role of catecholaminergic neurones terminating in the diagonal band of Broca, medial preoptic nucleus and median eminence. J Endocrinol 148:291-301
Grattan, D R; Park, S K; Selmanoff, M (1995) Orchidectomy and NMDA increase GnRH secretion as measured by push-pull perfusion of rat anterior pituitary. Am J Physiol 268:E685-92
Grattan, D R; Selmanoff, M (1994) Prolactin- and testosterone-induced inhibition of LH secretion after orchidectomy: role of preoptic and tuberoinfundibular gamma-aminobutyric acidergic neurones. J Endocrinol 143:165-74
Park, S K; Grattan, D R; Selmanoff, M (1993) Differential effects of adrenalectomy on the prolactin-induced suppression of LH and FSH secretion after castration in male rats. J Reprod Fertil 99:209-17

Showing the most recent 10 out of 20 publications