Tang M, Lau C E, Falk J L
Department of Psychology, Rutgers University, New Brunswick, New Jersey.
J Pharmacol Exp Ther. 1988 Sep;246(3):1053-60.
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.
为评估长期给予咪达唑仑（8-氯-6-（2-氟苯基）-1-甲基-4H-咪唑并[1,5-a][1,4]苯二氮䓬）对辨别性运动控制的影响，训练大鼠用爪子握住一个力传感器，使其在一个力带的上下限之间持续保持1.5秒，以便每次输送一粒食物颗粒。急性剂量的咪达唑仑（0.75 - 3.0毫克/千克，皮下注射）损害了运动表现指标以及会话工作率，后者是一种镇静指标。将大鼠分为不同组，分别在每次实验前（预给药组）或每次实验后（给药后组）给予长期咪达唑仑注射，或在每次实验前给予赋形剂（赋形剂组）。给药后组和赋形剂组表明，长期在实验后给予咪达唑仑、其撤药过程或单纯时间推移，均未改变运动表现。预给药组受到了影响，尽管对工作率下降的完全耐受性在长期给药（3.0毫克/千克）后迅速形成，但对运动损害的耐受性即使在4个月后仍不完全。对给药后组进行咪达唑仑的实验前药物探查发现，尽管对工作率下降的耐受性已经形成，但对咪达唑仑损害运动表现的能力并未形成耐受性。在对预给药组进行咪达唑仑长期注射的阶段，省略咪达唑仑或用Ro 15 - 1788拮抗它的实验会话，导致运动表现得到改善（药物清除效应）。Ro 15 - 1788并未引发戒断反应，尽管在长期给药4个月后单纯撤药确实扰乱了预给药组的运动表现。随后的实验会话显示运动表现有显著改善，恢复到了原来的、慢性给药前的基线水平。
