Central effects of 1,4-butanediol are mediated by GABA(B) receptors via its conversion into gamma-hydroxybutyric acid.
The aliphatic alcohol 1,4-butanediol in converted into gamma-hydroxybutyric acid (GHB) via two enzymatic steps: first, it is oxidised by alcohol dehydrogenase in gamma-hydroxybutyraldehyde; second, the latter is transformed, likely by aldehyde dehydrogenase, into GHB. Initially, the present study compared the sedative/hypnotic effect of GHB and 1,4-butanediol, measured as loss of righting reflex. 1,4-Butanediol was more potent than GHB, presumably because of a more rapid penetration of the blood brain barrier. Further alcohol dehydrogenase inhibitors, 4-methylpyrazole and ethanol, totally prevented the sedative/hypnotic effect of 1,4-butanediol; the aldehyde dehydrogenase inhibitor disulfiram partially blocked the sedative/hypnotic effect of 1,4-butanediol. Finally, the sedative/hypnotic effect of 1,4-butanediol was antagonised by the GABA(B) receptor antagonists, SCH 50911 [(2S)(+)-5,5-dimethyl-2-morpholineacetic acid] and CGP 46381 [(3-aminopropyl)(cyclohexylmethyl)phosphinic acid], but not by the putative GHB receptor antagonist NCS-382 (6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylideneacetic acid), indicating that it is mediated by GABA(B) but not GHB receptors. Taken together, these results suggest that the sedative/hypnotic effect of 1,4-butanediol is mediated by its conversion in vivo into GHB which, in turn, binds to GABA(B) receptors. Accordingly 1,4-butanediol, unlike GHB, failed to displace [(3)H]GHB and [(3)H]baclofen in brain membranes.
Carai
Mauro A M
MA
Neuroscienze S.c.a r.l., Via Palabanda 9, I-09123 Cagliari, Italy. mauro.carai@ns.crs4.it
Colombo
Giancarlo
G
Reali
Roberta
R
Serra
Salvatore
S
Mocci
Ignazia
I
Castelli
M Paola
MP
Cignarella
Giorgio
G
Gessa
Gian Luigi
GL
D000818:Animals; D002072:Butylene Glycols / Q000378:metabolism* / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D006885:Hydroxybutyrates / Q000378:metabolism* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000378:metabolism*; D012890:Sleep / Q000187:drug effects / Q000502:physiology
D002072:Butylene Glycols; D004791:Enzyme Inhibitors; D006885:Hydroxybutyrates; D018080:Receptors, GABA-B; C111420:4-hydroxybutyric acid; D000431:Ethanol; C039681:1,4-butanediol