The Role of Gaba_A Receptors in the Neural Systems of the Ventromedial Hypothalamus-Nucleus Infundibular Region in the Control of GnRH Release in Ewes during Follicular Phase

Abstract

To examine the role of the GABA_A receptor mediating systems in the control of gonadotropin releasing hormone (GnRH) release from the ventromedial-infundibular region (VEN/NI) of the hypothalamus of ewes during the follicular phase of the estrous cycle, the extracellular concentrations of GnRH, β-endorphin (B-END), noradrenaline (NE), dopamine (DA), and their metabolites MHPG, DOPAC and concentration of luteinizing hormone (LH) in blood plasma were quantified during local stimulation or blockade of GABA_A receptors with muscimol and bicuculline, respectively. Stimulation of GABA_A receptors attenuated GnRH and LH release, increased β-endorphin outflow and dopaminergic activity but had no evident effect on noradrenergic activity. Blockade of GABA_A receptors decreased β-endorphin release but had no evident effect on the extracellular concentration of GnRH, LH levels in the blood and catecholaminergic activity. It is suggested that suppression of GnRH/LH release under muscimol treatment may result from activation of GABA_A receptors on GnRH nerve terminals and through GABA_A receptor mechanism activated β-endorphinergic and dopaminergic neurons in the VEN/NI. Lack of changes in NE and MHPG concentration during stimulation or blockade of GABA_A receptors suggests, that during the follicular phase of the estrous cycle the noradrenergic system in the VEN/NI is not involved in the control of GnRH/LH release by GABA.

Hypothalamus - GABA - GnRH - B-END - catecholamines

References

• 1 Anderson R, Mitchell R. Effect of GABA receptor agonists on [³H] dopamine release from median eminence and pituitary neuromediate lobe.  Eur J Pharmacol. 1985;  115 109-112
• 2 Anderson S T, Walsh J P, Tillet Y, Clarke I J, Curlevis J D. Dopaminergic input to the ventromedial hypothalamus facilitates the estrogen-induced luteinizing hormone surge in ewes.  Neuroendocrinology. 2001;  73 91-101
• 3 Barraclough C, Wise P. The role of catecholamines in the regulation of pituitary luteinizing hormone and follicle stimulating hormone secretion.  Endocrine Rev. 1982;  3 91-119
• 4 Bilger M, Heger S, Brann D W, Paredes A, Ojeda S R. A conditional tetracycline - regulated increase in gamma amino butyric acid production near luteinizing hormone releasing hormone nerve terminals disrups estrous cyclicity in the rat.  Endocrinology. 2001;  142 2102-2114
• 5 Bourguignon J P, Gérard A, Purnelle G, Czajkowski V, Yamanaka C, Lemaitre M, Rigo J M, Moonen G, Franchimont P. Duality of glutamatergic and gabaergic control of pulsatile GnRH secretion by rat hypothalamic explants: I. Effects of antisense digodeoxynucleotides using explants including or excluding the preoptic area.  J Neuroendocrinology. 1997;  9 183-191
• 6 Chomicka L K, Woliñska-Witort E, Przekop F. Release of LHRH, β-endorphin and dopamine by the nucleus infundibularis-median eminence during the estrous cycle in the ewe.  Eur J Endocrinol. 1994;  130 (Supp 2) 43
• 7 Conover C D, Kuljis R O, Rabii J, Advis J P. Β-endorphin regulation of luteinizing hormone-releasing hormone at median eminence in ewes: immunocytochemical and physiological evidence.  Neuroendocrinology. 1993;  57 1182-1195
• 8 Curlevis J D, Naylor A M, Rhind S M, Mc Neilly A S. Effect of beta-endorphin on pulsatile luteinizing hormone and prolactin secretion during the follicular phase in the ewe.  J Neuroendocrinol. 1991;  3 123-127
• 9 Domański E, Chomicka L K, Ostrowska A, Gajewska A, Mateusiak K. Release of luteinizing hormone-releasing hormone, β-endorphin and noradrenaline by the nucleus infundibularis/median eminence during periovulatory period in sheep.  Neuroendocrinology. 1991;  54 151-158
• 10 Domański E, Gajewska A, Kochman H, Masiukiewicz E, Rzeszotarska B, Kochman K. Production of antibody specific against mammalian LHRH decapeptide.  Endocrinol Pol. 1994;  45 147-153
• 11 Donoso A O, Löpez F J, Negro-Vilar A. Cross-talk between excitatory and inhibitory amino acids in the regulation of luteinizing hormone-releasing hormone secretion.  Endocrinology. 1992;  131 1559-1561
• 12 Feleder C, Jarry H, Leonhardt S, Wuttke W, Moguilevsky J A. The gabaergic control of gonadotropin-releasing hormone secretion in male rats during sexual maturation involves effects on hypothalamic excitatory and inhibitory amino acid systems.  Neuroendocrinology. 1996;  64 305-312
• 13 Ferreira S A, Scott C J, Kuehl D C, Jackson G L. Differential regulation of luteinizing hormone release by γ-aminobutyric acid receptor subtypes in the arcuate-ventromedial region of the castrated ram.  Endocrinology. 1996;  137 3453-3460
• 14 Fiber J M, Etgen A M. GABA augments basal and electrically stimulated ³H-noradrenaline release in hypothalamic, preoptic area and cortical slices of the female rats.  Neurochem Int. 1997;  3 769-780
• 15 Fiber J M, Etgen A M. Evidence that GABA augmentation of norepinephrine release is mediated by interneurons.  Brain Res. 1998;  790 329-333
• 16 Goodman R L, Robinson J E, Kendrick K M, Dyer R G. Is the inhibitory action of estradiol on luteinizing hormone pulse frequency in anestrous ewes mediated by noradrenergic neurons in the preoptic area?.  Neuroendocrinology. 1995;  61 284-292
• 17 Hales T G, Sanderson M J, Charles A C. GABA has excitatory actions on GnRH-secreting immortalized hypothalamic (GT1 - 7) neurons.  Neuroendocrinology. 1994;  59 297-308
• 18 Herbison A E, Dyer R G. Effect on luteinizing hormone secretion of GABA receptor modulation in the preoptic area of the rat brain.  Neuroendocrinology. 1991;  53 317-323
• 19 Herbison A E. Estrogen regulation of GABA transmission in the rat preoptic area.  Brain Res Bull. 1997;  44 321-326
• 20 Herbison A E. Multimodal influence of estrogen upon gonadotropin-releasing hormone neurons.  Endocrine Rev. 1998;  19 302-330
• 21 Horvath T L, Naftolin F, Leranth C. Luteinizing hormone-releasing hormone and gamma-aminobutyric acid neurons in the medial preoptic area are synaptic targets of dopamine axons originating in anterior periventricular areas.  J Neuroendocrinology. 1993;  5 71-79
• 22 Jarry H, Leonhardt S, Wuttke W. Gamma-aminobutyric acid neurons in the preoptic/anterior hypothalamic area are synchronize the phasic activity of the gonadotropin-releasing hormone pulse generator in ovariectomized rats.  Neuroendocrinology. 1991;  53 261-267
• 23 Jarry H, Perschl A, Wuttke W. Further evidence that preoptic anterior hypothalamic GABAergic neurons are part of the GnRH pulse generator.  Acta Endocrinol. 1998;  118 573-579
• 24 Leonhardt S, Seong J Y, Kim K, Thorun Y, Wuttke W. Activation of central GABA-A but not GABA-B receptors rapidly reduces pituitary LH release and GnRH gene expression in the preoptic/anterior hypothalamic area of ovariectomized rats.  Neuroendocrinology. 1995;  61 655-662
• 25 Leonhardt S, Böning B, Luft H, Wuttke W, Jarry H. Activation of gene expression of the γ-aminobutyric acid rather than the glutamatergic system in the preoptic area during the preovulatory gonadotropin surge of the rat.  Neuroendocrinology. 2000;  71 8-15
• 26 Leshin L S, Malven P V. Radioimmunoassay for β-endorphin (lipotropin) in unextracted plasma from sheep.  Domestic Animal Endocrinol. 1984;  1 175-188
• 27 Martinez de la Escalera G, Choi A LH, Weiner R J. Biphasic gabaergic regulation of GnRH secretion in GT₁ cell lines.  Neuroendocrinology. 1994;  59 420-425
• 28 Merriam G R, Wachter K W. Algorithms for the study of episodic hormone secretion.  (Endocrinol Metab 6) Am J Physiol. 1982;  243 E310-E318
• 29 Navarro C E, Cabrera R J, Donoso A O. Interaction between glutamate and GABA on ³H ^- noradrenaline release from rat hypothalamus.  Brain Res Bull. 1995;  37 119-122
• 30 Nikolarakis K E, Loeffler J-PH, Almeida O FX, Herz A. Pre- and postsynaptic actions of GABA on the release of hypothalamic gonadotropin-releasing hormone (GnRH).  Brain Res Bull. 1988;  21 677-683
• 31 Przekop F, Mateusiak K, Stupnicka E, Romanowicz K, Domañski E. Suppressive effect of β-endorphin on the secretion of cortisol under stress conditions in sheep.  Exp Clin Endocrinol. 1990;  95 307-314
• 32 Robinson J E, Kendrick K M, Lambart C E. Changes in the release of gamma-aminobutyric acid and catecholamines in the preoptic/septal area prior to and during the preovulatory surge of luteinizing hormone in the ewe.  J Neuroendocrinology. 1991;  3 393-399
• 33 Robinson J E, Kendrick K M. Inhibition of luteinizing hormone secretion in the ewe by progesterone: associated changes in the release of gamma-aminobutyric acid and noradrenaline in the preoptic area as measured by intracranial microdialysis.  J Neuroendocrinology. 1992;  4 231-236
• 34 Robinson J E. Gamma amino-butyric acid and the control of GnRH secretion in sheep.  J Reprod Fertil Supp.. 1995;  49 221-230
• 35 Scott C J, Clarke I J. Inhibition of luteinizing hormone secretion in ovariectomized ewes during the breeding season by γ-aminobutyric acid (GABA) is mediated by GABA-A receptors, but not GABA-B receptors.  Endocrinology. 1993 a;  132 1789-1796
• 36 Scott C J, Clarke I J. Evidence that changes in the function of the subtypes of the receptors for γ-aminobutyric acid may be involved in the seasonal changes in the negative-feedback effects of estrogen on gonadotropin-releasing hormone secretion and plasma luteinizing hormone levels in the ewe.  Endocrinology. 1993 b;  133 2904-2912
• 37 Sin J A, Skynner M J, Pape J R, Herbison A E. Late postnatal reorganization of GABA receptor signalling in native GnRH neurons.  Eur J Neurosci. 2000;  12 3497-3504
• 38 Stupnicki R, Madej A. Radioimmunoassay of LH in blood plasma of farm animals.  Endokrinologie. 1976;  68 6-13
• 39 Taniyama K, Niwa M, Kataoka Y, Yamashita K. Activation of protein kinase C suppresses the gamma-aminobutyric acid β receptor-mediated inhibition of vesicular release of noradrenaline and acetylocholine.  J Neurochem. 1992;  58 1239-1245
• 40 Tomaszewska-Zaremba D, Przekop F, Mateusiak K. The involvement of GABA_A receptors in the control of GnRH and β-endorphin release, and catecholaminergic activity in the ventromedial-infundibular region of hypothalamus in anestrous ewes.  J Physiol Pharmacol. 2001;  52 489-500
• 41 Traczyk W, Przekop F. Methods of investigation of the function of the hypothalamus and hypophysis in chronic experiments in sheep.  Acta Physiol Pol. 1963;  14 217-226
• 42 Viguie C, Caraty A, Locatelli A, Malpaux B. Regulation of luteinizing hormone-releasing hormone (LHRH) secretion by melatonin in the ewe. Simultaneous delayed increase in LHRH and luteininzing hormone pulse secretion.  Biol Reprod. 1995;  52 1114-1120
• 43 Wagner E J, Goudreau J L, Moore K E, Lookingland K J. GABAergic regulation of tuberoinfundibular dopaminergic neurons in the male rat.  Brain Res. 1994;  659 194-200
• 44 Welento J, Steyn S, Milart Z. Observation on the stereotaxic configuration of the hypothalamus nuclei in sheep.  Anat Anz. 1969;  124 1-27