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Evidence that -Aminobutyric Acid Is Part of the Neural Circuit Mediating Estradiol Negative Feedback in Anestrous Ewes

Department of Physiology and Pharmacology (A.L.B., S.L.H., J.M.C., S.M.L., H.J.B., C.J.M., M.V., S.R.S., C.C.N., R.L.G.), West Virginia University, Morgantown, West Virginia 26506; Departments of Anatomy and Cell Biology (M.N.L.) and Physiology and Pharmacology (L.M.C.), University of Western Ontario, London, Ontario, Canada N6A 5C1; and Department of Cellular and Physiological Sciences (J.H.S.), British Columbia University, Vancouver, British Columbia, Canada V6T 1Z3

Address all correspondence and requests for reprints to: Robert L. Goodman, Department of Physiology and Pharmacology, P.O. Box 9229, West Virginia University, Morgantown, West Virginia 26506-9229. E-mail: bgoodman{at}hsc.wvu.edu.

Seasonal anestrus in ewes is driven by an increase in response to estradiol (E₂) negative feedback. Compelling evidence indicates that inhibitory A15 dopaminergic (DA) neurons mediate the increased inhibitory actions of E₂ in anestrus, but these neurons do not contain estrogen receptors. Therefore, we have proposed that estrogen-responsive afferents to A15 neurons are part of the neural circuit mediating E₂ negative feedback in anestrus. This study examined the possible role of afferents containing -aminobutyric acid (GABA) and nitric oxide (NO) in modulating the activity of A15 neurons. Local administration of NO synthase inhibitors to the A15 had no effect on LH, but GABA receptor ligands produced dramatic changes. Administration of either a GABA_A or GABA_B receptor agonist to the A15 increased LH secretion in ovary-intact ewes, suggesting that GABA inhibits A15 neural activity. In ovariectomized anestrous ewes, the same doses of GABA receptor agonist had no effect, but combined administration of a GABA_A and GABA_B receptor antagonist to the A15 inhibited LH secretion. These data are consistent with the hypothesis that endogenous GABA release within the A15 is low in ovary-intact anestrous ewes and elevated after ovariectomy. Using dual immunocytochemistry, we observed that GABAergic varicosities make close contacts on to A15 neurons and that A15 neurons contain both the GABA_A-1 and the GABA_B-R1 receptor subunits. Based on these data, we propose that in anestrous ewes, E₂ inhibits release of GABA from afferents to A15 DA neurons, increasing the activity of these DA neurons and thus suppressing episodic secretion of GnRH and LH.

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				S. R. Singh, S. M. Hileman, J. M. Connors, C. J. McManus, L. M. Coolen, M. N. Lehman, and R. L. Goodman Estradiol Negative Feedback Regulation by Glutamatergic Afferents to A15 Dopaminergic Neurons: Variation with Season Endocrinology, October 1, 2009; 150(10): 4663 - 4671. [Abstract] [Full Text] [PDF]