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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.
- Source :
- Journal of Neurochemistry; 11/1/2003, Vol. 87 Issue 3, p722, 11p
- Publication Year :
- 2003
-
Abstract
- Two γ-hydroxybutyric acid (GHB) analogues, trans -γ-hydroxycrotonic acid (t-HCA) and γ-(p-methoxybenzyl)-γ-hydroxybutyric acid (NCS-435) displaced [<superscript>3</superscript> H]GHB from GHB receptors with the same affinity as GHB but, unlike GHB, failed to displace [<superscript>3</superscript> H]baclofen from GABA<subscript>B</subscript> 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-[<superscript>35</superscript> S]thiotriphospate) [<superscript>35</superscript> S]GTPγS binding both in cortex homogenate and cortical slices, t-HCA and NCS-435 were ineffective up to 1 m m concentration. GHB and baclofen effect was suppressed by the GABA<subscript>B</subscript> antagonist CGP 35348 but not by the GHB receptor antagonist NCS-382. Perfused into rat hippocampus, 500 n m and 1 m m 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 µ m ) locally perfused into hippocampus increased extracellular glutamate; this effect was inhibited by NCS-382 (10 µ m ) but not by CGP 35348 (500 µ m ). The results indicate that GHB-induced G protein activation and reduction of glutamate levels are GABA<subscript>B</subscript> -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<subscript>B</subscript> -mediated. The GHB analogues constitute important tools for understanding the physiological role of endogenous GHB and its receptor. [ABSTRACT FROM AUTHOR]
- Subjects :
- GAMMA-hydroxybutyrate
HIPPOCAMPUS (Brain)
GABA antagonists
LABORATORY rats
Subjects
Details
- Language :
- English
- ISSN :
- 00223042
- Volume :
- 87
- Issue :
- 3
- Database :
- Complementary Index
- Journal :
- Journal of Neurochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 11054723
- Full Text :
- https://doi.org/10.1046/j.1471-4159.2003.02037.x