The long-term objective of this research program is to determine the neuroendocrine mechanisms regulating LH and prolactin secretion in mammals. Proposed studies examine hypothalamic mechanisms by which testosterone (T) and estradiol-17beta (E(2)) plus progesterone (P(4)) may exert their negative feedback action on tonic LH secretion in adult male and female rats. While the concept of steroid negative feedback was first posited in the 1930's, the identity of the neurons acted upon by negative feedback steroids and their relationship to the GnRH neurons are not known with certainty. Our current focus is to determine the physiological role of steroid-addressed GABAergic neurons situated in the diagonal band of Broca at the level of the organum vasculosum of the lamina terminalis [DBB(ovlt)], the dorsomedial aspect of the medial preoptic nucleus (MPNdm), and the tuberoinfundibular GABAergic (TIGA) neurons, in the regulation of LH secretion. These GABAergic neurons are known to concentrate sex steroids or to express sex steroid receptor, GABAergic neurons are known to synapse on GnRH neurons, and GnRH neurons in situ recently have been shown to express GABA(A)beta(3) receptor subunit mRNA. The principal working hypothesis under investigation is that steroid- sensitive rostral hypothalamic and tuberoinfundibular GABAergic neurons mediate the negative feedback effects of gonadal steroids on GnRH neurons. Proposed research is focused on four specific aims to determine: (1) whether ovariectomy decreases preoptic and tuberoinfundibular GABAergic neurotransmission which is prevented by physiological, negative feedback concentrations of E2 + P(4), (2) whether microinfusions of steroid receptor antagonists or antisense oligonucleotides to steroid receptor mRNAs block the effects of sex steroids on GABA turnover and GAD(65 or 67) mRNA expression in these steroid-sensitive brain regions, (3) whether steroid receptor antagonist microinfusions into these steroid-sensitive brain regions increase GnRH release which is prevented by co-infusion of GABA and GABA(A) receptor agonists, and (4), whether gonadectomy decreases GAD(65 or 67) mRNA in steroid receptor-containing GABAergic neurons, and whether gonadectomy increases GABA(A)beta(3) receptor subunit mRNA expression in GnRH neurons. This research will further our understanding of the hypothalamic mechanism regulating tonic LH secretion in male and female rats, and the way in which negative, and perhaps positive, feedback steroids affect this mechanism.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Reproductive Endocrinology Study Section (REN)
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University of Maryland Baltimore
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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

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