Ade. Barbosa et Gs. Morato, Influence of neurosteroids on the development of rapid tolerance to ethanol in mice, EUR J PHARM, 431(2), 2001, pp. 179-188
Our recent study demonstrated that neurosteroids might either facilitate or
block chronic tolerance to the incoordinating effects of ethanol. The pres
ent study investigated the effects of neurosteroids on the development of r
apid tolerance to ethanol-induced motor impairment using the N-methyl-D-asp
artate (NMDA) receptor antagonist dizocilpine [(+)-MK-801] or the gamma -am
inobutyric acid (GABA) type A (GABA(A)) receptor agonist muscimol. Male Swi
ss mice were pretreated with pregnenolone sulfate (0.03 to 0.15 mg/kg) or d
ehydroepiandrosterone sulfate (0.05 to 0.20 mg/kg) before administration of
ethanol (1.9 or 2.25 g/kg) and tested with the rota-rod apparatus. Twenty-
four hours later, all animals were re-tested with the rota-rod after receiv
ing the same dose of ethanol. Pretreatment with pregnenolone sulfate or wit
h dehydroepiandrosterone sulfate significantly facilitated the acquisition
of tolerance. However, the administration of (+)-MK-801 reversed the stimul
atory action of pregnenolone sulfate but did not affect the actions of dehy
droepiandrosterone sulfate on ethanol tolerance. Pretreatment with pregneno
lone sulfate or dehydroepiandrosterone sulfate prevented the inhibitory act
ion of muscimol on tolerance development. Taken together, our results sugge
st that neurosteroids may stimulate the development of rapid tolerance to e
thanol and that GABA(A) and NMDA receptor systems may be involved in these
actions. (C) 2001 Elsevier Science B.V. All rights reserved.