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Quantitative analyses of drug combinations using a benzodiazepine discrimination procedure in rhesus monkeys

Adverse effects of benzodiazepines limit their clinical use; these effects might be reduced without altering therapeutic effects by administering other positive GABAA modulators (i.e., neuroactive steroids) concurrently with benzodiazepines. To begin to understand combined effects of positive modulators, the ability of flumazenil to attenuate effects of 2 benzodiazepines, midazolam and flunitrazepam, administered alone or in combination, was studied in 4 monkeys discriminating midazolam. Although receptor theory predicts that concurrent administration of benzodiazepines will not alter interactions with their receptors, this notion has not been rigorously tested. Midazolam, flunitrazepam or a combination of the 2 drugs produced >80% midazolam‐lever responding, and flumazenil dose‐dependently antagonized each effect. Schild analyses yielded slopes that did not deviate from unity, regardless of whether benzodiazepines were administered alone or concurrently, indicating simple, competitive interactions; the pA2 value for flumazenil was 7.58. Thus, these data conform to theory in a quantifiable manner, allowing other notions regarding drug/drug interactions to be tested. Combinations of drugs acting at different sites, such as benzodiazepines and neuroactive steroids, could be studied to develop strategies for reducing adverse effects. Supported by USPHS grant DA09157 and DA17918 (CPF).