| Selective gamma-hydroxybutyric acid receptor ligands increase extracellular glutamate in the hippocampus, but fail to activate G protein and to produce the sedative/hypnotic effect of gamma-hydroxybutyric acid. | |
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MedLine Citation:
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PMID: 14535954 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Two gamma-hydroxybutyric acid (GHB) analogues, trans-gamma-hydroxycrotonic acid (t-HCA) and gamma-(p-methoxybenzyl)-gamma-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]GTPgammaS 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 microm) locally perfused into hippocampus increased extracellular glutamate; this effect was inhibited by NCS-382 (10 microm) but not by CGP 35348 (500 microm). 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. |
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Authors:
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M Paola Castelli; Luca Ferraro; Ignazia Mocci; Francesca Carta; Mauro A M Carai; Tiziana Antonelli; Sergio Tanganelli; Giorgio Cignarella; Gian Luigi Gessa |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Journal of neurochemistry Volume: 87 ISSN: 0022-3042 ISO Abbreviation: J. Neurochem. Publication Date: 2003 Nov |
Date Detail:
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Created Date: 2003-10-10 Completed Date: 2003-11-24 Revised Date: 2004-11-17 |
Medline Journal Info:
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Nlm Unique ID: 2985190R Medline TA: J Neurochem Country: England |
Other Details:
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Languages: eng Pagination: 722-32 Citation Subset: IM |
Affiliation:
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Neuroscienze S.c.a r.l., Cagliari, Italy. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Autoradiography Benzocycloheptenes / pharmacology Binding, Competitive / drug effects Brain Chemistry Extracellular Space / metabolism GABA Antagonists / pharmacology GTP-Binding Proteins / drug effects, metabolism* Glutamic Acid / metabolism* Guanosine 5'-O-(3-Thiotriphosphate) / pharmacokinetics Hippocampus / drug effects, metabolism* Hydroxybutyrates / pharmacology* Hypnotics and Sedatives / pharmacology Ligands Male Mice Mice, Inbred DBA Microdialysis Organophosphorus Compounds / pharmacology Rats Rats, Sprague-Dawley Receptors, Cell Surface / drug effects, metabolism* Reflex / drug effects |
| Chemical | |
Reg. No./Substance:
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0/4-hydroxybutyric acid receptor; 0/Benzocycloheptenes; 0/GABA Antagonists; 0/Hydroxybutyrates; 0/Hypnotics and Sedatives; 0/Ligands; 0/Organophosphorus Compounds; 0/Receptors, Cell Surface; 0/gamma-(4-methoxybenzyl)-gamma-hydroxybutyric acid; 123690-79-9/CGP 35348; 131733-92-1/NCS 382; 37589-80-3/Guanosine 5'-O-(3-Thiotriphosphate); 4013-24-5/4-hydroxy-2-butenoic acid; 56-86-0/Glutamic Acid; 591-81-1/4-hydroxybutyric acid; EC 3.6.1.-/GTP-Binding Proteins |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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