IngentaConnect Selective -hydroxybutyric acid receptor ligands increase extracel...

Authors: Castelli, M. Paola¹; Ferraro, Luca²; Mocci, Ignazia¹; Carta, Francesca³; Carai, Mauro A. M.³; Antonelli, Tiziana²; Tanganelli, Sergio²; Cignarella, Giorgio⁴; Gessa, Gian Luigi

Source: Journal of Neurochemistry, Volume 87, Number 3, November 2003 , pp. 722-732(11)

Publisher: Blackwell Publishing

Abstract:

Two 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 GABA_B 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 GABA_B 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 GABA_B-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 GABA_B-mediated. The GHB analogues constitute important tools for understanding the physiological role of endogenous GHB and its receptor.

Keywords: GABAB; GHB analogues; glutamate; GTPγS binding; hippocampus; NCS-382

Document Type: Research article

DOI: 10.1046/j.1471-4159.2003.02037.x

Affiliations: 1: Neuroscienze S.c.a r.l., Cagliari, Italy 2: Department of Clinical and Experimental Medicine, Pharmacology Section, University of Ferrara, Ferrara, Italy 3: `Bernard B. Brodie' Department of Neuroscience 4: Institute of Pharmaceutical and Toxicological Chemistry, University of Milan, Milan, Italy

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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