gamma-Hydroxybutyrate modulation of glutamate levels in the hippocampus: an in vivo and in vitro study

J Neurochem. 2001 Sep;78(5):929-39. doi: 10.1046/j.1471-4159.2001.00530.x.


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 (CA1) 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 microM 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 microM) but not by the GABA(B) receptor antagonist CGP-35348 (500 microM). Furthermore, the gamma-hydroxybutyric acid (1 mM)-induced reduction in CA1 glutamate levels was counteracted by NCS-382 (10 microM), 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 microM). 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anesthetics, Intravenous / pharmacology*
  • Animals
  • Anticonvulsants / pharmacology
  • Benzocycloheptenes / pharmacology
  • Calcium / pharmacology
  • Consciousness / physiology
  • Extracellular Space / metabolism
  • GABA Antagonists / pharmacology
  • Glutamic Acid / metabolism*
  • Hippocampus / drug effects*
  • Hippocampus / metabolism*
  • In Vitro Techniques
  • Male
  • Microdialysis
  • Organophosphorus Compounds / pharmacology
  • Potassium / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Sodium Oxybate / pharmacology*
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology
  • Synaptosomes / drug effects
  • Synaptosomes / metabolism
  • Tetrodotoxin / pharmacology


  • Anesthetics, Intravenous
  • Anticonvulsants
  • Benzocycloheptenes
  • GABA Antagonists
  • Organophosphorus Compounds
  • NCS 382
  • Glutamic Acid
  • Tetrodotoxin
  • Sodium Oxybate
  • CGP 35348
  • Potassium
  • Calcium