Selective γ‐hydroxybutyric acid receptor ligands increase extracellular glutamate in the hippocampus, but fail to activate G protein and to produce the sedative/hypnotic effect of γ‐hydroxybutyric acid

• DOI: 10.1046/j.1471-4159.2003.02037.x
• Publication Date: 2003-10-16T03:51:18Z
• Authors: M. Paola Castelli; Luca Ferraro; Ignazia Mocci; Francesca Carta; Mauro A. M. Carai; Tiziana Antonelli; Sergio Tanganelli; Giorgio Cignarella; Gian Luigi Gessa
• Keywords: Male; Microdialysis; Glutamic Acid; Hydroxybutyrates; Ligands; Binding, Competitive; Hippocampus; GABA Antagonists; Mice; 03 medical and health sciences; Organophosphorus Compounds; GTP-Binding Proteins; Animals; Hypnotics and Sedatives; Brain Chemistry; 0303 health sciences; GABAB; GHB analogues; glutamate; GTPgammaS binding; hippocampus; NCS-382.; Rats; Benzocycloheptenes; GABAB; GHB analogues; glutamate; GTPcS binding; hippocampus; NCS-382.; Guanosine 5'-O-(3-Thiotriphosphate); Mice, Inbred DBA; Autoradiography; GABA(B); GHB analogues; glutamate ; GTP gamma S binding; hippocampus; NCS-382; Extracellular Space

AbstractTwo γ‐hydroxybutyric acid (GHB) analogues, trans‐γ‐hydroxycrotonic acid (t‐HCA) and γ‐(p‐methoxybenzyl)‐γ‐hydroxybutyric acid (NCS‐435) displaced [3H]GHB from GHB receptors with the same affinity as GHB but, unlike GHB, failed to displace [3H]baclofen from GABAB receptors. The effect of the GHB analogues, GHB and baclofen, on G protein activity and hippocampal extracellular glutamate levels was compared. While GHB and baclofen stimulated 5′‐O‐(3‐[35S]thiotriphospate) [35S]GTPγS binding both in cortex homogenate and cortical slices, t‐HCA and NCS‐435 were ineffective up to 1 mm concentration. GHB and baclofen effect was suppressed by the GABAB antagonist CGP 35348 but not by the GHB receptor antagonist NCS‐382. Perfused into rat hippocampus, 500 nm and 1 mm GHB increased and decreased extracellular glutamate levels, respectively. GHB stimulation was suppressed by NCS‐382, while GHB inhibition by CGP 35348. t‐HCA and NCS‐435 (0.1–1000 µm) locally perfused into hippocampus increased extracellular glutamate; this effect was inhibited by NCS‐382 (10 µm) but not by CGP 35348 (500 µm). The results indicate that GHB‐induced G protein activation and reduction of glutamate levels are GABAB‐mediated effects, while the increase of glutamate levels is a GHB‐mediated effect. Neither t‐HCA nor NCS‐435 reproduced GHB sedative/hypnotic effect in mice, confirming that this effect is GABAB‐mediated. The GHB analogues constitute important tools for understanding the physiological role of endogenous GHB and its receptor.