Acute Increase of GABAergic Neurotransmission Exerts a Stimulatory Effect on GnRH Gene Expression in the Preoptic/Anterior Hypothalamic Area of Ovariectomized, Estrogen- and Progesterone-Treated Adult Female Rats

Abstract

Although γ-aminobutyric acid (GABA) is known to play an important role in the regulation of GnRH release from the hypothalamus, GABAergic action on hypothalamic GnRH gene expression is poorly understood. The present study aims to evaluate the effects of several GABAergic compounds on GnRH mRNA and serum LH levels at the times of LH surge induced by estrogen plus progesterone treatment in long-term ovariectomized adult rats. Animals received either aminooxyacetic acid (AOAA, an inhibitor of GABA catabolism, i.p.), muscimol (GABA-A type agonist, i.c.v.) or baclofen (GABA-B type agonist, i.c.v.) 2 h prior to sacrifice. GnRH mRNA in the preoptic/anterior hypothalamic area and serum LH levels were determined by Northern blot analysis and LH radioimmunoassay, respectively. All of three GABA mimetics blocked the LH surge induced by estrogen plus progesterone in a dose-dependent manner. However, inhibition of GABA catabolism with AOAA in a dose range of 10-100 mg/kg b.w. increased GnRH mRNA level by 30%. Activation of GABA-A receptor with muscimol at a low dose (5 nmol) but not at high doses (10 and 30 nmol) elevated GnRH mRNA levels by 60% over the control value. Activation of GABA-B receptor with baclofen augmented GnRH mRNA levels in a dose-dependent manner. These observations indicate that acute increase of GABAergic neurotransmission may differentially regulate the release and GnRH gene expression depending on its receptor subtypes.

Growth Hormone Secretion after Baclofen Administration in Different Phases of the Menstrual Cycle in Healthy Women

“…In these two phases of the menstrual cycle, the plasma E 2 concentrations were significantly higher in comparison with the early follicular phase, showing a possible relationship between baclofen-induced GH response and estrogens. These findings suggest, as reported by others [22], that there is a modulation of estrogens on the GH release induced by stimulation of GABA B receptors. In addition, although the plasma E 2 levels were significantly lower during the luteal phase than during the periovulatory phase, the mean plasma GH values detected during luteal phase showed a baclofen-induced GH release significantly higher in comparison with that detected during the periovulatory phase.…”

GABA_B1 Knockout Mice Reveal Alterations in Prolactin Levels, Gonadotropic Axis, and Reproductive Function

“…GABA has been shown to influence the hypothalamic-hypophyseal-ovarian axis through GABA A and GABA B receptor activity [11,12,13,14,46,47,48]. Furthermore, GABA B Rs are expressed in gonadotropin-releasing hormone (GnRH) neurons [49, 50], in the pituitary [7, 18, 20], and in the ovary [16, 51, 52].…”

Lack of functional GABAB receptors alters GnRH physiology and sexual dimorphic expression of GnRH and GAD-67 in the brain

“…Whether the alteration in GAD expression and neurotransmitter levels we observed in the present work are also found at neonatal stages of development is still unknown. In addition, whether it is the increase in GAD-67 expression and GABA and glutamate contents in GABA B1 KO females that in turn alters GnRH expression, as previously suggested (46,52), or whether these are parallel phenomena remains to be determined. Also, it has to be taken into account that an increase in GABA and glutamate contents does not necessarily mean an increase in neurotransmitter release.…”