Midazolam Attenuates Esketamine-Induced Overactive Behaviors in Mice Before the Sedation, but Not During the Recovery

Esketamine showed more potency, more rapid recovery from anesthesia, and less psychotomimetic side effects when compared with ketamine. However, the patients still experience psychotomimetic side effects of esketamine. In order to investigate whether midazolam can attenuate the esketamine-induced overactive behaviors and neuronal hyperactivities, midazolam 0, 40, 80, and 120 mg/kg combined with esketamine 50 mg/kg were administrated on Kunming mice to assess the behaviors changes during anesthesia. The indicators, including action time, duration of agitation before the sedation, duration of sedation, duration of loss of pedal withdrawal reaction (PWR), duration of loss of righting reaction (RR), duration of agitation during the recovery, and recovery time, were monitored for up to 3-4 h after intraperitoneal administration. The results demonstrated that midazolam 40, 80, and 120 mg/kg efficiently decreased the esketamine-induced overactive behaviors including ataxia, excitation, and catalepsy before sedation. Midazolam and esketamine synergically improved the anesthesia quality assessed by PWR and RR. However, even high doses of midazolam were not able to suppress the esketamine-induced psychotomimetic effects during the recovery.