Chronic ethanol administration to rodents and humans produces tolerance to ethanol and cross-tolerance to benzodiazepines and barbiturates. In contrast, ethanol-dependent rats are sensitized to the anticonvulsant effects of 3α,5α-THP and 3α,5α-THDOC (Cagetti et al. 2004; Devaud et al. 1996; 1998). GABAA receptor sensitivity to 3α,5α-THP and 3α,5α-THDOC is enhanced in the cortex, but sensitivity to alphaxalone is reduced in the hippocampus (Cagetti et al. 2004) of ethanol-dependent rats, likely due to adaptations in GABAA receptor expression described above. Since ethanol-dependent rats are sensitized to anticonvulsant actions of neuroactive steroids, this class of compounds may be useful during ethanol withdrawal. Indeed, neuroactive steroid therapy may have advantages over benzodiazepine therapy since benzodiazepines exhibit cross-tolerance with ethanol. Further studies are needed to explore this possibility.
