We now report an expansion of our findings on neuroactive steroids. Our data in preclinical models of anxiety associated with drug dependence and in preclincal models of epilepsy support the contention that these compounds have potential for the clinical treatment of anxiety disorders, drug dependence withdrawal states, and in drug resistant epilepsies. Our findings show that neuroactive steroids are both qualitatively and quantitatively superior to a host of other positive allosteric modulators of GABA. In addition, work with a series of novel and potential antiepileptic agents, we have found good efficacy and side-effect profiles for several (e.g., gabapentin) against drug- resistant cocaine seizures. This finding distinguished them from other compounds which lack efficacy (e.g., diazepam, phenobarbital, etc.). Mechanistic deductions led to the conclusion that compounds which enhance GABA at post-synaptic targets demonstrate the greatest efficacies and the best predicted therapeutic windows.
