Pre- and postsynaptic actions of GABA on the release of hypothalamic gonadotropin-releasing hormone (GnRH).
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.
Nikolarakis
K E
KE
Department of Neuropharmacology, Max-Planck-Institut für Psychiatrie, Planegg-Martinsried, F.R.G.
Loeffler
J P
JP
Almeida
O F
OF
Herz
A
A
D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000502:physiology; D004723:Endorphins / Q000502:physiology; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009411:Nerve Endings / Q000187:drug effects / Q000502:physiology; D010906:Pituitary Hormone-Releasing Hormones / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013268:Stimulation, Chemical; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D004723:Endorphins; D010906:Pituitary Hormone-Releasing Hormones; D005680:gamma-Aminobutyric Acid; D003346:Corticotropin-Releasing Hormone