Alphaxalone and epiallopregnanolone in rats trained to discriminate ethanol

Background: Neurosteroids with a 3 alpha-hydroxy orientation share pharmacological effects with ethanol, increase in brain after ethanol administration, and may mediate ethanol effects. 3beta-hydroxy neurosteroids antagonize in vitro and some, but not all in vivo effects of ethanol and 3 alpha-hydroxy neurosteroids.

Methods: We assessed the discriminative stimulus and rate altering effects of alphaxalone, a 3 alpha-hydroxy neurosteroid, and epiallopregnanolone, a 3beta-hydroxy neurosteroid, in rats trained to discriminate either 0.8 g/kg or 1.2 g/kg ethanol. The ability of epiallopregnanolone to antagonize the discriminative stimulus or rate-altering effects of ethanol or alphaxalone was also assessed.

Results: Ethanol had similar discriminative ED50s (0.5 g/kg) in both groups; however rats trained with the lower ethanol dose were more sensitive to rate-decreasing effects of ethanol. Alphaxalone occasioned ethanol-appropriate responding in both training groups, although less effectively in rats trained on the lower ethanol dose (maximum 65% versus 80% ethanol-appropriate responding). No difference in sensitivity to the rate-decreasing effects of alphaxalone was present between groups. Epiallopregnanolone did not reliably occasion ethanol-appropriate responding in either training group, and rats trained on the lower ethanol dose were slightly more sensitive to epiallopregnanolone rate decreasing effects. Epiallopregnanolone did not alter any effects of ethanol or alphaxalone.

Conclusions: Our results agree with previous reports that 3 alpha-hydroxy neurosteroids occasion ethanol-appropriate responding, while 3beta-hydroxy neurosteroids do not; as well as reports showing no antagonism of the discriminative stimulus or rate-suppressant effects of ethanol or 3 alpha-hydroxy neurosteroids by 3beta-hydroxy neurosteroids. Results of the present study demonstrate that ethanol and 3 alpha-hydroxy neurosteroids share discriminative stimulus effects. However, these results are inconsistent with the hypothesis that such neurosteroids mediate the discriminative stimulus of ethanol.