Regulation of glutamate release via NMDA and 5-HT1A receptors in guinea pig dentate gyrus

The regulation by 5-HT1A and N-methyl-D-aspartate (NMDA) receptors on the endogenous glutamate release was investigated in slices of guinea pig dentate gyrus. The release of glutamate was increased dose-dependently by the 5-HT1A receptor antagonist, NAN-190 at 0.01 to 300 nM, but was not affected by the 5-HT1A receptor agonist, 8-OH-DPAT even at 100 nM. The release of glutamate evoked by 0.1 mu M NAN-190 was Ca2+-dependent, tetrodotoxin sensitive and inhibited significantly by 8-OH-DPAT at 1, 10 and 100 nM. These results suggest that the 5-HT1A receptor, which is located postsynaptically on glutamatergic neurons, is involved in the inhibitory regulation of glutamate release. The release of glutamate evoked by 200 mu M NMDA from dentate gyrus was inhibited significantly by pretreatment with 8-OH-DPAT at 1, 10 and 100 nM. The release of glutamate evoked by 0.1 mu M NAN-190 was inhibited significantly by pretreatment with MK-801 at 1 and 10 mu M, a selective non-competitive NMDA receptor antagonist. The release of glutamate evoked by NMDA at 25 and 75 mu M from dentate gyrus was augmented by the concurrent application of 1 nM NAN-190. We propose that the glutamate release from guinea pig dentate gyrus is regulated both by the postsynaptic 5-HT1A receptor in an inhibitory manner and by the NMDA receptor in a stimulatory manner.