γ-hydroxybutyrate modulation of glutamate levels in the hippocampus:: an in vivo and in vitro study

The effect of gamma -hydroxybutyric acid on extracellular glutamate levels in the hippocampus was studied by microdialysis in freely moving rats and in isolated hippocampal synaptosomes. Intra-hippocampal (CAI) perfusion with gamma -hydroxybutyric acid (10 nm-1 mM) concentration-dependently influenced glutamate levels: gamma -hydroxybutyric acid (100 and 500 nM) increased glutamate levels; 100 and 300 muM concentrations were ineffective; whereas the highest 1 mM concentration reduced local glutamate levels. The stimulant effect of gamma -hydroxybutyric acid (100 nM) was suppressed by the locally co-perfused gamma -hydroxybutyric acid receptor antagonist NCS-382 (10 muM) but not by the GABA(B) receptor antagonist CGP-35348 (500 Lm). Furthermore, the gamma -hydroxybutyric acid (1 mM)-induced reduction in CA1 glutamate levels was counteracted by NCS-382 (10 muM), and it was also reversed into an increase by CGP-35348. Given alone, neither NCS-382 nor CGP-35348 modified glutamate levels. In hippocampal synaptosomes, gamma -hydroxybutyric acid (50 and 100 nM) enhanced both the spontaneous and K+-evoked glutamate efflux, respectively, both effects being counteracted by NCS-382 (100 nM), but not by CGP-35348 (100 muM). These findings indicate that gamma -hydroxybutyric acid exerts a concentration-dependent regulation of hippocampal glutamate transmission via two opposing mechanisms, whereby a direct gamma -hydroxybutyric acid receptor mediated facilitation is observed at nanomolar gamma -hydroxybutyric acid concentrations, and an indirect GABA(B) receptor mediated inhibition predominates at millimolar concentrations.