Midazolam and discriminative motor control: chronic administration, withdrawal and modulation by the antagonist Ro 15-1788.
To evaluate the effects of chronic midazolam (8-chloro-6-(2-fluorophenyl)-1-methyl-4H- imidazo[1,5-a][1,4]benzodiazepine) administration on discriminative motor control, rats were trained to hold a force transducer operated with a paw so that it remained between upper and lower limits of a force band for a continuous 1.5-sec period to deliver each food pellet. Acute doses of midazolam (0.75-3.0 mg/kg s.c.) impaired indices of motor performance as well as session work rate, a measure of sedation. Separate groups received chronic midazolam injections either pressession (Before Group) or postsession (After Group), or presession vehicle (Vehicle Group). The After and Vehicle Groups indicated that neither chronic postsession midazolam, its withdrawal, nor time alone, changed motor performance. The Before Group was affected, and although complete tolerance to work-rate decrements developed rapidly to chronic dosing (3.0 mg/kg), tolerance to motor impairment was incomplete even after 4 months. Presession drug probes with midazolam to the After Group revealed that, although tolerance to work-rate decrement had developed, no tolerance had developed with respect to the capacity for midazolam to impair motor performance. During the chronic phase of midazolam injection to the Before Group, sessions that omitted midazolam, or antagonized it with Ro 15-1788, led to improved motor performance (a drug-purge effect). Precipitated withdrawal was not produced by Ro 15-1788, although simple drug withdrawal did disrupt Before Group motor performance after 4 months of chronic dosing. Ensuing sessions showed a marked improvement in motor performance which returned to the original, prechronic, base-line level.