gamma-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 i n isolated hippocampal synaptosomes. Intra-hippocampal (CAI) perfusion with gamma -hydroxybutyric acid (10 nm-1 mM) concentration-dependently influenc ed 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 stimulan t effect of gamma -hydroxybutyric acid (100 nM) was suppressed by the local ly co-perfused gamma -hydroxybutyric acid receptor antagonist NCS-382 (10 m uM) but not by the GABA(B) receptor antagonist CGP-35348 (500 Lm). Furtherm ore, the gamma -hydroxybutyric acid (1 mM)-induced reduction in CA1 glutama te levels was counteracted by NCS-382 (10 muM), and it was also reversed in to an increase by CGP-35348. Given alone, neither NCS-382 nor CGP-35348 mod ified 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 -hydroxy butyric acid exerts a concentration-dependent regulation of hippocampal glu tamate transmission via two opposing mechanisms, whereby a direct gamma -hy droxybutyric acid receptor mediated facilitation is observed at nanomolar g amma -hydroxybutyric acid concentrations, and an indirect GABA(B) receptor mediated inhibition predominates at millimolar concentrations.