TY - JOUR
T1 - γ-Hydroxybutyrate modulation of glutamate levels in the hippocampus
T2 - An in vivo and in vitro study
AU - Ferraro, Luca
AU - Tanganelli, Sergio
AU - O'Connor, William Thomas
AU - Francesconi, Walter
AU - Loche, Antonella
AU - Gessa, Gian Luigi
AU - Antonelli, Tiziana
PY - 2001
Y1 - 2001
N2 - 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.
AB - 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.
KW - CA1
KW - CGP-35348
KW - Conscious rat
KW - Microdialysis
KW - NCS-382
KW - Synaptosomes
UR - http://www.scopus.com/inward/record.url?scp=0034839415&partnerID=8YFLogxK
U2 - 10.1046/j.1471-4159.2001.00530.x
DO - 10.1046/j.1471-4159.2001.00530.x
M3 - Article
C2 - 11553667
AN - SCOPUS:0034839415
SN - 0022-3042
VL - 78
SP - 929
EP - 939
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 5
ER -