Methylphenidate Reversal of Dexmedetomidine-Induced Versus Ketamine-Induced Sedation in Rats

Abstract

BACKGROUND: Dexmedetomidine and ketamine have long elimination half-lives in humans and have no clinically approved reversal agents. Methylphenidate enhances dopaminergic and noradrenergic neurotransmission by inhibiting reuptake transporters for these arousal-promoting neurotransmitters. Previous studies in rats demonstrated that intravenous methylphenidate induces emergence from isoflurane and propofol general anesthesia. These 2 anesthetics are thought to act primarily through enhancement of inhibitory Gamma-aminobutyric acid type A (GABAA) receptors. In this study, we tested the behavioral and neurophysiological effects of methylphenidate in rats after low and high doses of dexmedetomidine (an alpha-2 adrenergic receptor agonist) and ketamine (an N-methyl-D-aspartate [NMDA] receptor antagonist) that induce sedation and unconsciousness, respectively. METHODS: All experiments used adult male and female Sprague-Dawley rats (n = 32 total) and all drugs were administered intravenously in a crossover, blinded experimental design. Locomotion after sedating doses of dexmedetomidine (10 µg/kg) or ketamine (10 mg/kg) with and without methylphenidate (5 mg/kg) was tested using the open field test (n = 16). Recovery of righting reflex after either high-dose dexmedetomidine (50 µg/kg) or high-dose ketamine (50 mg/kg) with and without methylphenidate (1–5 mg/kg) was assessed in a second cohort of rats (n = 8). Finally, in a third cohort of rats (n = 8), frontal electroencephalography (EEG) was recorded for spectral analysis under both low and high doses of dexmedetomidine and ketamine with and without methylphenidate. RESULTS: Low-dose dexmedetomidine reduced locomotion by 94% in rats. Methylphenidate restored locomotion after low-dose dexmedetomidine (rank difference = 88.5, 95% confidence interval [CI], 70.8–106) and the effect was blocked by coadministration with a dopamine D1 receptor antagonist (rank difference = 86.2, 95% CI, 68.6–104). Low-dose ketamine transiently attenuated mobility by 58% and was not improved with methylphenidate. Methylphenidate did not affect the return of righting reflex latency in rats after high-dose dexmedetomidine nor ketamine. Frontal EEG analysis revealed that methylphenidate reversed spectral changes induced by low-dose dexmedetomidine (F [8,87] = 3.27, P = .003) but produced only transient changes after high-dose dexmedetomidine. Methylphenidate did not induce spectral changes in the EEG after low- or high-dose ketamine. CONCLUSIONS: Methylphenidate reversed behavioral and neurophysiological correlates of sedation, but not unconsciousness, induced by dexmedetomidine. In contrast, methylphenidate did not affect sedation, unconsciousness, nor EEG signatures in rats after ketamine. These findings suggest that methylphenidate may be efficacious to reverse dexmedetomidine sedation in humans.