Chronobiological Study of the Pharmacological Response of Rats to Combination Ketamine–Midazolam

Abstract

Ketamine is commonly administered in combination with benzodiazepines to achieve surgical anaesthesia in rats. The aim of the present study was to analyze the pharmacological response of the combination ketamine–midazolam injected intraperitoneally at different times of day to rats. The study was conducted in July 2003, during the winter in the Southern hemisphere. Female prepuberal Sprague-Dawley rats synchronized to a 12 h light:12 h dark cycle (light, 07:00–19:00 h) were used as experimental animals. A combination treatment of ketamine (40 mg/kg) and midazolam (2 mg/kg) was administered to five different clock-time groups of rats (n = 7/group). Duration of the latency period, ataxia, loss-of-righting reflex (LRR), post-LRR ataxia, and total pharmacological response were assessed by visual assessment. Significant treatment-time differences were detected in the duration of LRR, post-LRR ataxia, and total pharmacological response duration. The longest pharmacological response occurred in rats injected during the light (rest) phase, and the shortest pharmacological response occurred in rats injected during the dark (activity) phase. Cosinor analysis documented circadian rhythmicity in the duration of post-LRR ataxia. The findings of the study indicate the duration of CNS-depression of the ketamine–midazolam combination exhibits treatment-time-dependent variation in the rat.