Nikolarakis K E, Loeffler J P, Almeida O F, Herz A
Department of Neuropharmacology, Max-Planck-Institut für Psychiatrie, Planegg-Martinsried, F.R.G.
Brain Res Bull. 1988 Oct;21(4):677-83. doi: 10.1016/0361-9230(88)90208-0.
The role of gamma-aminobutyric acid (GABA) in the regulation of gonadotropin hormone-releasing hormone (GnRH) release was studied using rat hypothalamic slices in vitro. Perifusion with GABA (10(-8)-10(-4) M) caused a dose-dependent increase in GnRH release. The GABAA receptor agonist isoguvacine (10(-5) M) also stimulated GnRH release, whereas the GABAB agonist baclofen (10(-6) M) had no effect. The specific GABAA antagonist SR95103 (10(-6) M) caused a reduction of basal GnRH release and completely blocked that induced by GABA (10(-4) M). When nerve transmission was blocked with tetrodotoxin (TTX, 10(-6) M), GnRH release was slightly reduced but the stimulatory effects of both GABA and isoguvacine were abolished. The GABA-induced stimulation of GnRH release was also prevented when the hypothalamic slices were treated with a corticotropin releasing hormone (CRH) antagonist (alpha-helical CRF9-41, 10(-6) M) or the opioid antagonist naloxone (10(-6) M). Treatment with CRH (10(-8) M) resulted in a decrease in GnRH release and this effect was not reversed in the presence of GABA. Finally, GABA was found to stimulate the release of the opioid peptides beta-endorphin, dynorphin and met-enkephalin. These results lead us to conclude that GABA exerts two opposing effects upon GnRH neuronal activity: it acts in an inhibitory fashion at GnRH nerve terminals and in a stimulatory fashion at GnRH perikarya; the latter might occur through GABAergic inhibition of CRH release and, therefore, of opioid peptide release. Lastly, all the effects of GABA upon GnRH release appear to be mediated through GABAA receptors.
利用体外培养的大鼠下丘脑切片研究了γ-氨基丁酸（GABA）在促性腺激素释放激素（GnRH）释放调节中的作用。用GABA（10⁻⁸ - 10⁻⁴ M）进行灌流导致GnRH释放呈剂量依赖性增加。GABAA受体激动剂异鹅去甲肾上腺素（10⁻⁵ M）也刺激GnRH释放，而GABAB激动剂巴氯芬（10⁻⁶ M）则无作用。特异性GABAA拮抗剂SR95103（10⁻⁶ M）导致基础GnRH释放减少，并完全阻断由GABA（10⁻⁴ M）诱导的释放。当用河豚毒素（TTX，10⁻⁶ M）阻断神经传递时，GnRH释放略有减少，但GABA和异鹅去甲肾上腺素的刺激作用均被消除。当下丘脑切片用促肾上腺皮质激素释放激素（CRH）拮抗剂（α-螺旋CRF9 - 41，10⁻⁶ M）或阿片类拮抗剂纳洛酮（10⁻⁶ M）处理时，GABA诱导的GnRH释放刺激也被阻止。用CRH（10⁻⁸ M）处理导致GnRH释放减少，并且在存在GABA的情况下这种作用没有逆转。最后，发现GABA刺激阿片肽β-内啡肽、强啡肽和甲硫脑啡肽的释放。这些结果使我们得出结论，GABA对GnRH神经元活动发挥两种相反的作用：它在GnRH神经末梢以抑制方式起作用，而在GnRH胞体处以刺激方式起作用；后者可能通过GABA能抑制CRH释放，进而抑制阿片肽释放而发生。最后，GABA对GnRH释放的所有作用似乎都是通过GABAA受体介导的。
