Glutamate agonists and [3H]GABA release from rat hippocampal slices: involvement of metabotropic glutamate receptors in the quisqualate-evoked release.

The effects of glutamate agonists and their selective antagonists on the Ca(2+)-dependent and independent releases of [3H]GABA from rat coronal hippocampal slices were studied in a superfusion system. The Ca(2+)-dependent release evoked by glutamate, kainate and N-methyl-D-aspartate (NMDA) gradually declined with time despite the continuous presence of the agonists. Quisqualate (QA) caused a sustained release which exhibited no tendency to decline within the 20-min period of stimulation. This release was enhanced in Ca(2+)-free medium. The release evoked by QA in Ca(2+)-containing medium was significantly inhibited by (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohept-5,10-imine hydrogen maleate (MK-801) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), showing that QA activates NMDA receptors directly or indirectly through (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors. The inhibition of MK-801 was slightly diminished and that of CNQX totally abolished in Ca(2+)-free medium. Verapamil inhibited the QA-activated release in both Ca(2+)-containing and Ca(2+)-free media. The effect of QA but not that of AMPA was blocked in Ca(2+)-free medium by L(+)-2-amino-3-phosphonopropionate (L-AP3), a selective antagonist of the metabotropic glutamate receptor. It is suggested that the sustained release of GABA is also mediated partly by activation of metabotropic receptors and mobilization of Ca2+ form intracellular stores.