Influence of neurosteroids on the development of rapid tolerance to ethanol in mice

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.