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

Luca Ferraro, Sergio Tanganelli, William Thomas O'Connor, Walter Francesconi, Antonella Loche, Gian Luigi Gessa, Tiziana Antonelli

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)929-939
Number of pages11
JournalJournal of Neurochemistry
Volume78
Issue number5
DOIs
Publication statusPublished - 2001
Externally publishedYes

Keywords

  • CA1
  • CGP-35348
  • Conscious rat
  • Microdialysis
  • NCS-382
  • Synaptosomes

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