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

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