γ‐Hydroxybutyrate modulation of glutamate levels in the hippocampus: an in vivo and in vitro study

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Abstract
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 GABAB 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 GABAB receptor mediated inhibition predominates at millimolar concentrations.