Drug dependence tests on a new anesthesia inducer, midazolam.

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Abstract
Drug dependence tests on a new intravenous anesthesia inducer midazolam were performed in comparison with triazolam in male cynomolgus monkeys utilizing the intravenous route of administration. 1) In the animals trained to self-administer sodium pentobarbital (0.6 .apprx. 1 mg/kg/inj) under FRI and FR10 reinforcement schedules, 0.01 midazolam and 0.001 mg/kg/inj triazolam maintained self-administration in more than 4 out 5 animals under FR1. Doses of 0.03 and 0.001 mg/kg/inj, respectively, were required under FR10. 2) The intradaily progressive ratio test revealed that midazolam maintained self-administration only weakly (equivalently as or more weakly than triazolam did). 3) Midazolam at 0.003 .apprx. 0.1 and triazolam at 0.0003 .apprx. 0.01 mg/kg/inj initiated self-administration, respectively, in 3 and 1 out of 4 naive animals, but the numbers of self-administration responses were only slightly higher than the vehicle control level. Pentobarbital at 0.1 .apprx. 3 mg/kg initiated self-administration in all of 4 animals with a high level of self-administration. 4) In the single dose suppression test in physically pentobarbital-dependent animals, and ED25 value of midazolam for the suppression of the withdrawal signs was 0.30 mg/kg, i.v., which was almost equivalent to that for the central nervous system depression (0.27 mg/kg, i.v.). This was in clear contrast to the results of triazolam and pentobarbital, of which the ED25 values for the suppression were lower than those for the central nervous system depression. 5) In naive animals, after the chronic administration of midazolam at 0.9, triazolam at 0.09, pentobarbital at 60 mg/kg/day (the doses inducing intermediate sedation) intravenously for 4 weeks, withdrawal signs were found respectively in 0, 1 and 3 out of 4 animals. After the chronic administration of higher doses of the compounds (1.2, 0.12 and 80 mg/kg/day) for 4 weeks, the withdrawal signs were found respectively in 1 and 2 out of 3 and 3 out of 4 animals. The benzodiazepine antagonist Ro 15-1788 (1 and 3 mg/kg, i.v.) precipitated clear withdrawal signs in none of 3 midazolam animals and 2 out of 3 triazolam animals. From these results, it can be concluded that the drug dependence liability of midazolam is within the range of those of most benzodiazepines.