Effect of epipregnanolone and pregnenolone sulfate on chronic tolerance to ethanol

The aim of the present study was to investigate the influence of neurosteroids on the development of tolerance to ethanol. Male Swiss mice were injected daily with the positive allosteric modulator of the gamma amino butyric acid-A (GABA(A)) receptor epipregnanolone (5beta-pregnan-3beta-ol-20-one; 0.15 mg/kg i.p.) or pregnenolone sulfate (5-pregnen-3beta-ol-20-one sulfate sodium; 0.08 mg/kg i.p.) - considered a negative allosteric modulator of this receptor and/or positive allosteric modulator of the N-methyl-D-aspartate (NMDA) receptor - 30 min before ethanol (2.5 g/kg i.p.). They were tested on the rota-rod apparatus, under continuous acceleration (1rpm/s), at 30, 60 and 90 min after ethanol injections for 5 days. The results showed that tolerance to the motor incoordinating effect of ethanol occurred on the fifth day of treatment when this effect was blocked by pretreatment with epipregnanolone. On the other hand, ethanol tolerance was enhanced by pretreatment with pregnenolone sulfate from the second to the fifth days of treatment. Taken together, our results suggest that neurosteroids can either stimulate or block the development of chronic tolerance to ethanol. Moreover, since neurosteroids can interact with GABA(A) or NMDA receptor systems, our results suggest the involvement of these systems in the actions of neurosteroids upon ethanol tolerance.