Among the pharmacological actions of gamma-hydroxybutyric acid (GHB), some may involve GABA,, receptor-mediated mechanisms. GHB, however, fails to directly interact with sites for agonists and modulators on the GABA(A) receptor complex. We hypothesized that, in vivo, GHB may interfere with GABA, receptor function by altering the brain concentrations of the neurosteroids 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolonc, AP) and 3alpha,21-dihydroxy-5alpha-pregnan-20-one (allotetrahydrodeoxycorticosterone, THDOC), positive allosteric modulators of GABA-gated chloride currents. In male Wistar rats, GHB dose-dependently (75-1000 mg/kg, i.p.) increased AP, THDOC and their precursors pregnenolone and progesterone in brain cortex and hippocampus. The increases of AP (4-5 fold) and THDOC (3-4 fold) elicited by 300 mg/kg GHB peaked between 30 and 90 min and abated by 180 min. The selective GABA(B) receptor antagonist SCH 50911 (50 mg/kg, i.p.) prevented the action of GHB, while the GABA(B) receptor agonist baclofen (5-10 mg/kg) mimicked it. NCS-382 (50 mg/kg, i.p.), the purported selective antagonist of the GHB receptor, failed to antagonize GHB, but at 300 mg/kg increased brain cortical neurosteroids to the same extent as 300 mg/kg GHB; coadtministration of GHB and NCS-382, however, failed to yield an additive effect. These results strongly suggest that GHB, via a GABA(B) receptor-mediated mechanism, increases the brain concentrations of neurosteroids, whose properties as amplifyers of the GABA-gated chloride conductances may play a role in the GABA, receptor-mediated pharmacological actions of GHB. (C) 2002 Elsevier Science Ltd. All rights reserved.
Barbaccia M.L., C.G. (2002). GABA(B) receptor-mediated increase of neurosteroids by gamma-hydroxybutyric acid. NEUROPHARMACOLOGY, 42(6), 782-791.
|Tipologia:||Articolo su rivista|
|Citazione:||Barbaccia M.L., C.G. (2002). GABA(B) receptor-mediated increase of neurosteroids by gamma-hydroxybutyric acid. NEUROPHARMACOLOGY, 42(6), 782-791.|
|IF:||Con Impact Factor ISI|
|Settore Scientifico Disciplinare:||Settore BIO/14|
|Revisione (peer review):||Sì, ma tipo non specificato|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/S0028-3908(02)00026-6|
|Stato di pubblicazione:||Pubblicato|
|Data di pubblicazione:||2002|
|Titolo:||GABA(B) receptor-mediated increase of neurosteroids by gamma-hydroxybutyric acid|
|Autori:||Barbaccia M.L., Colombo G., Affricano D., Carai M.A.M., Vacca G., Melis S., Purdy R.H., Gessa G.L.|
|Appare nelle tipologie:||01 - Articolo su rivista|