GABA(B) receptors in neuroendocrine regulation

Abstract

Gamma-amino butyric acid (GABA), in addition to being a metabolic intermediate and the main inhibitory neurotransmitter in the synaptic cleft, is postulated as a neurohormone, a paracrine signaling molecule, and a trophic factor. It acts through pre- and post-synaptic receptors, named GABA(A) and GABA(C) (ionotropic receptors) and GABA(B) (metabotropic receptor). Here we reviewed the participation of GABA(B) receptors in the regulation of the hypothalamic-pituitary-gonadal axis, using physiological, biochemical, and pharmacological approaches in rats, as well as in GABA(B1) knock-out mice, that lack functional GABA(B) receptors. Our general conclusion indicates that GABA(B )receptors participate in the regulation of pituitary hormone secretion acting both in the central nervous system and directly on the gland. PRL and gonadotropin axes are affected by GABA(B) receptor activation, as demonstrated in the rat and also in the GABA(B1) knock-out mouse. In addition, hypothalamic and pituitary GABA(B) receptor expression is modulated by steroid hormones. GABA participation in the brain control of pituitary secretion through GABA(B) receptors depends on physiological conditions, being age and sex critical factors.These results indicate that patients receiving GABA(B) agonists/antagonists should be monitored for possible endocrine side effects.

Fig. 1

Effect of Baclofen on stress and suckling-induced prolactin secretion. (a) Dose response effect of Baclofen (BACL) (2.5, 5, and 10 mg/kg) on prolactin secretion induced by immobilization stress in male rats. Numbers inside or above columns indicate number of rats per group. * P < 0.05. (Published in Proc Soc Exp Biol Med 197: 337–341:1991). (b) Effect of baclofen on PRL secretion and milk yied after 25 min suckling. Numbers inside columns indicate number of animals per group. * P < 0.05, compared to saline controls. Published in Proc Soc Exp Biol Med 183: 358–362:1986. Both figures are reproduced with the permission of the Society for Experimental Biology and Medicine

Fig. 2

Phaclofen antagonizes baclofen-induced PRL secretion inhibition in monolayer cultures of adenohypophyseal dispersed cells after 2-h incubation. Results are expressed as the percentage of control values, considering the control as 100%. a: significantly different from control values, b: significantly different from baclofen values. Published in Neuroendocrinology 56:687–693:1992. Reproduced with the permission of S. Karger AG, Basel

Fig. 3

Effect of baclofen on forskolin-induced cAMP production in anterior pituitary cells from proestrous rats. C: control, B: baclofen 1.10⁻⁵ M, PTX: Pertussis Toxin (150 ng/ml, 20 h), 2HO-S: 2 hydroxysaclophen 1.10⁻⁴ M, F: forskolin 0.5 μM. a: significantly different from control values, b: significantly different from F, F-B-PTX, and F-B-2HO-S. n: four experiments. Published in Neuroendocrinology 73:334–343:2001. Reproduced with the permission of S. Karger AG, Basel

Fig. 4

Integration of GABA_B1a receptor subunit inmunoblots of female and male developing and adult rat anterior pituitary membranes. Results in arbitrary units (AU) are the mean ± SE of 4–5 independent samples and are expressed as the relation of each subunit with regard to the syntaxin control. a: significantly different from 12 days onwards; b: significantly different from 20 days onwards. * significantly different from males at a certain age. For all cases: P < 0.05 or less

Fig. 5

GABA_B1 receptor subunit expression in anterior hypophysis from 8-day-old animals under different treatments determined by Western Blot with specific antisera. 8F: 8-day-old control females, 8F1TP: 8-day-old females injected with 1 μg TP on days 1–4 of life, 8F100TP: 8-day-old females treated with 100 μg of TP on the day of birth, 8F-Flut: 8-day-old female pups from Flutamide injected mothers, 8M: 8-day-old control males, 8MC: 8-day-old males castrated on the day of birth, 8M-Flut: 8-day-old males from Flutamide injected mothers, 8MC-Flut: 8-day-old males from Flutamide injected mothers and castrated on the day of birth. Upper panel: Representative Western Blot for GABA_B1a and GABA_B1b subunit and α syntaxin expression. Ctx: cortex membranes used as positive controls. MW: molecular weight markers. Lower panel: Data are expressed as the ratio of GABA_B1 subunit expression to α syntaxin expression. Number of samples per group: 8F = 12, 8F1TP = 6: 8F100TP = 12, 8F-Flut = 6, 8M = 12, 8MC = 12, 8M-Flut = 6 and 8MC-Flut = 10. Results were analyzed by two-way ANOVA: interaction: ns, indicating that both splice variants follow the same pattern of expression, factor subunit: P < 0.001, indicating that GABA_B1a is always more abundant than GABA_B1b, factor treatment: P < 0.001 or less; a: different from 8F, b: different from 8F1TP, c: different from 8F.Flut, d: different from 8M-Flut, e: different from 8MC-Flut, f: different from 8F100TP, g: different from 8M, h: different from 8MC. Published in Neuroendocrinology 80:129–142:2004. Reproduced with the permission of S. Karger AG, Basel

Fig. 6

Representative profiles illustrating the disruption of estrous cyclicity in GABA_B1 ^−/− mice compared to wild-type (WT) controls, GABA_B1^+/+ (upper panel). Days in each phase of the estrous cycle (%) in GABA_B1^+/+ and GABA_B1 ^−/− mice (lower panel). % days of estrous cycle: Student’s t test. * P < 0.001, significantly different from WT mice. Published in Neuroendocrinology 82:294–305:2005. Reproduced with the permission of S. Karger AG, Basel