Endogenous γ-aminobutyric acid (GABA)A receptor active neurosteroids and the sedative/hypnotic action of γ-hydroxybutyric acid (GHB):: A study in GHB-S (sensitive) and GHB-R (resistant) rat lines

In the rat brain, gamma-hydroxybutyric-acid (GHB) increases the concentrations of 3 alpha-hydroxy,5 alpha-pregnan-20-one (allopregnanolone, 3 alpha,5 alpha-THP) and 3 alpha,21-dihydroxy,5 alpha-pregnan-20-one (allotetrahydrodeoxycorticosterone/3 alpha,5 alpha THDOC), two neurosteroids acting as positive allosteric modulators of gamma-aminobutyric acid (GABA)A receptors. This study was aimed at assessing whether neurosteroids play a role in GHB-induced loss of righting reflex (LORR). Basal and GHB-stimulated brain concentrations of endogenous 3 alpha,5 alpha-THP and 3 alpha,5 alpha-THDOC were analyzed in two rat lines, GHB-sensitive (GHB-S) and GHB-resistant (GHB-R), selectively bred for opposite sensitivity to GHB-induced sedation/hypnosis. Basal neurosteroid concentrations were similar in brain cortex of the two rat lines. However, in male GHB-S rats, administration of GHB (1000 mg/kg, i.p., 30 min) increased brain cortical concentrations of 3 alpha,5 alpha-THP and 3 alpha,5 alpha-THDOC 7- and 2.5-fold, respectively, whilst male GHB-R animals displayed only a 4- and 2-fold increase, respectively. In GHB-S rats this increase lasted up to 90 min and declined 180 min following GHB administration, a time course that matches LORR onset and duration. In contrast, in GHB-R rats, which failed to show GHB-induced LORR, brain cortical 3 alpha,5 alpha-THP and 3 alpha,5 alpha-THDOC had returned to control values within 90 min. At onset of LORR, a similar increase in brain cortical levels of 3 alpha,5 alpha-THP and 3 alpha,5 alpha-THDOC (2-3-fold) was observed in GHB-S female rats and in the few female GHB-R rats that lost the righting reflex after GHB administration, but not in female GHB-R rats failing to show LORR. Sub-hypnotic doses (7.5 and 12.5 mg/kg, i.p.) of pregnanolone, administered 10 min before GHB, dose-dependently facilitated the expression of GHB-induced LORR in GHB-R male rats. These results suggest that the GHB-induced increases of brain 3 alpha,5 alpha-THP and 3 alpha,5 alpha-THDOC concentrations are implicated in the eliciting of the sedative/hypnotic action of GHB. (c) 2005 Elsevier Ltd. All rights reserved.