Benzodiazepine and neuroactive steroid combinations in rats: anxiolytic-like and discriminative stimulus effects

Benzodiazepines are effective anxiolytics, hypnotics, and anticonvulsants but unwanted side effects, including abuse potential, limit their use. A possible strategy to increase the therapeutic index of this drug class is to combine benzodiazepines with neuroactive steroids. The present study evaluated the extent to which combinations of benzodiazepines (triazolam, clonazepam) and neuroactive steroids (pregnanolone, ganaxolone) induced additive, supra-additive, or infra-additive effects in an elevated zero maze and a drug discrimination procedure in rats. Male Sprague-Dawley rats (N = 7/group) were placed into an elevated zero maze apparatus following injections of multiple doses of triazolam and pregnanolone, alone and combined, or clonazepam and ganaxolone, alone and combined. These drugs/drug combinations also were evaluated in rats (N = 8) trained to discriminate triazolam (0.1 mg/kg, i.p.) from vehicle. Drug interactions were evaluated using isobolographic and dose-addition analysis. In the elevated zero maze, all drugs engendered dose-dependent increases in time spent in the open quadrant when administered alone. Triazolam and pregnanolone, as well as clonazepam and ganaxolone combinations produced additive or supra-additive effects depending on the fixed-proportion that was tested. In triazolam discrimination, all drugs engendered dose-dependent increases in triazolam-lever responding. In combination, triazolam and pregnanolone and clonazepam and ganaxolone produced predominantly additive discriminative stimulus effects, except for one fixed proportion of clonazepam and ganaxolone which had supra-additive effects. Although drug interactions depended on the constituent drugs, the combination tested, and the behavioral endpoint; a combination was identified that would be predicted to result in supra-additive anxiolytic-like effects with predominantly additive discriminative stimulus effects.