γ-Hydroxybutyrate modulation of glutamate levels in the hippocampus: An in vivo and in vitro study

The effect of γ-hydroxybutyric acid on extracellular glutamate levels in the hippocampus was studied by microdialysis in freely moving rats and in isolated hippocampal synaptosomes. Intra-hippocampal (CA1) perfusion with γ-hydroxybutyric acid (10 nM-1 mM) concentration-dependently influenced glutamate levels: γ-hydroxybutyric acid (100 and 500 nM) increased glutamate levels; 100 and 300 μM concentrations were ineffective; whereas the highest 1 mM concentration reduced local glutamate levels. The stimulant effect of γ-hydroxybutyric acid (100 nM) was suppressed by the locally co-perfused γ-hydroxybutyric acid receptor antagonist NCS-382 (10 μM) but not by the GABA_B receptor antagonist CGP-35348 (500 μM). Furthermore, the γ-hydroxybutyric acid (1 mM)-induced reduction in CA1 glutamate levels was counteracted by NCS-382 (10 μM), 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, γ-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 μM). These findings indicate that γ-hydroxybutyric acid exerts a concentration-dependent regulation of hippocampal glutamate transmission via two opposing mechanisms, whereby a direct γ-hydroxybutyric acid receptor mediated facilitation is observed at nanomolar γ-hydroxybutyric acid concentrations, and an indirect GABA_B receptor mediated inhibition predominates at millimolar concentrations.