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.
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.
Castelli
M Paola
MP
Neuroscienze S.c.a r.l., Cagliari, Italy.
Ferraro
Luca
L
Mocci
Ignazia
I
Carta
Francesca
F
Carai
Mauro A M
MA
Antonelli
Tiziana
T
Tanganelli
Sergio
S
Cignarella
Giorgio
G
Gessa
Gian Luigi
GL
D000818:Animals; D001345:Autoradiography; D001567:Benzocycloheptenes / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D001923:Brain Chemistry; D005110:Extracellular Space / Q000378:metabolism; D018756:GABA Antagonists / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D006885:Hydroxybutyrates / Q000494:pharmacology*; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008024:Ligands; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D017551:Microdialysis; D009943:Organophosphorus Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*; D012018:Reflex / Q000187:drug effects
C039403:4-hydroxybutyric acid receptor; D001567:Benzocycloheptenes; D018756:GABA Antagonists; D006885:Hydroxybutyrates; D006993:Hypnotics and Sedatives; D008024:Ligands; D009943:Organophosphorus Compounds; D011956:Receptors, Cell Surface; C478820:gamma-(4-methoxybenzyl)-gamma-hydroxybutyric acid; C066471:NCS 382; C111420:4-hydroxybutyric acid; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D018698:Glutamic Acid; C035142:4-hydroxy-2-butenoic acid; C066430:CGP 35348; D019204:GTP-Binding Proteins