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 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.
Ferraro
L
L
Department of Clinical and Experimental Medicine, Pharmacology Section, University of Ferrara, Ferrara, Italy.
Tanganelli
S
S
O'Connor
W T
WT
Francesconi
W
W
Loche
A
A
Gessa
G L
GL
Antonelli
T
T
D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001567:Benzocycloheptenes / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D003243:Consciousness / Q000502:physiology; D005110:Extracellular Space / Q000378:metabolism; D018756:GABA Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D017551:Microdialysis; D009943:Organophosphorus Compounds / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012978:Sodium Oxybate / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology
D018686:Anesthetics, Intravenous; D000927:Anticonvulsants; D001567:Benzocycloheptenes; D018756:GABA Antagonists; D009943:Organophosphorus Compounds; C066471:NCS 382; D018698:Glutamic Acid; D013779:Tetrodotoxin; D012978:Sodium Oxybate; C066430:CGP 35348; D011188:Potassium; D002118:Calcium