Methylphenidate Reversal of Dexmedetomidine-Induced Versus Ketamine-Induced Sedation in Rats.
Journal
Anesthesia and analgesia
ISSN: 1526-7598
Titre abrégé: Anesth Analg
Pays: United States
ID NLM: 1310650
Informations de publication
Date de publication:
07 Aug 2024
07 Aug 2024
Historique:
medline:
7
8
2024
pubmed:
7
8
2024
entrez:
7
8
2024
Statut:
aheadofprint
Résumé
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. 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. 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. 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.
Sections du résumé
BACKGROUND
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
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
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
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.
Identifiants
pubmed: 39110627
doi: 10.1213/ANE.0000000000007085
pii: 00000539-990000000-00894
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : National Institute of Health
ID : R01-GM126155
Informations de copyright
Copyright © 2024 International Anesthesia Research Society.
Déclaration de conflit d'intérêts
Conflicts of Interest, Funding: Please see DISCLOSURES at the end of this article.
Références
Wieber J, Gugler R, Hengstmann JH, Dengler HJ. Pharmacokinetics of ketamine in man. Anaesthesist. 1975;24:260–263.
Lam SW, Alexander E. Dexmedetomidine use in critical care. AACN Adv Crit Care. 2008;19:113–120.
Iirola T, Aantaa R, Laitio R, et al. Pharmacokinetics of prolonged infusion of high-dose dexmedetomidine in critically ill patients. Crit Care. 2011;15:R257.
Aho M, Erkola O, Kallio A, Scheinin H, Korttila K. Comparison of dexmedetomidine and midazolam sedation and antagonism of dexmedetomidine with atipamezole. J Clin Anesth. 1993;5:194–203.
Granholm M, McKusick BC, Westerholm FC, Aspegren JC. Evaluation of the clinical efficacy and safety of dexmedetomidine or medetomidine in cats and their reversal with atipamezole. Vet Anaesth Analg. 2006;33:214–223.
Verghese C, Abdijadid S. Methylphenidate. StatPearls; 2022.
Solt K, Cotten JF, Cimenser A, Wong KF, Chemali JJ, Brown EN. Methylphenidate actively induces emergence from general anesthesia. Anesthesiology. 2011;115:791–803.
Chemali JJ, Van Dort CJ, Brown EN, Solt K. Active emergence from propofol general anesthesia is induced by methylphenidate. Anesthesiology. 2012;116:998–1005.
Zhang Y, Gui H, Hu L, Li C, Zhang J, Liang X. Dopamine D1 receptor in the NAc shell is involved in delayed emergence from isoflurane anesthesia in aged mice. Brain Behav. 2021;11:e01913.
Gui H, Liu C, He H, Zhang J, Chen H, Zhang Y. Dopaminergic projections from the ventral tegmental area to the nucleus accumbens modulate sevoflurane anesthesia in mice. Front Cell Neurosci. 2021;15:671473.
Bao WW, Xu W, Pan GJ, et al. Nucleus accumbens neurons expressing dopamine D1 receptors modulate states of consciousness in sevoflurane anesthesia. Curr Biol. 2021;31:1893–1902.e5.
Taylor NE, Van Dort CJ, Kenny JD, et al. Optogenetic activation of dopamine neurons in the ventral tegmental area induces reanimation from general anesthesia. Proc Natl Acad Sci U S A. 2016;113:12826–12831.
Vincent KF, Solt K. Modulating anesthetic emergence with pathway-selective dopamine signaling. Curr Opin Anaesthesiol. 2023;36:468–475.
Wang J, Miao X, Sun Y, Li S, Wu A, Wei C. Dopaminergic system in promoting recovery from general anesthesia. Brain Sci. 2023;13:538.
Kenny JD, Chemali JJ, Cotten JF, et al. Physostigmine and methylphenidate induce distinct arousal states during isoflurane general anesthesia in rats. Anesth Analg. 2016;123:1210–1219.
Percie du Sert N, Hurst V, Ahluwalia A, et al. The ARRIVE guidelines 2.0: updated guidelines for reporting animal research. PLoS Biol. 2020;18:e3000410.
Kato R, Zhang ER, Mallari OG, et al. D-amphetamine rapidly reverses dexmedetomidine-induced unconsciousness in rats. Front Pharmacol. 2021;12:668285.
Bokil H, Andrews P, Kulkarni JE, Mehta S, Mitra PP. Chronux: a platform for analyzing neural signals. J Neurosci Methods. 2010;192:146–151.
Fox J, Weisberg S. An {R} Companion to Applied Regression. 3rd ed. Sage; 2019.
Wickham H. ggplot2: Elegant Graphics for Data Analysis. Springer-Verlag; 2016.
Kay M, Elkin LA, Higgins JJ, Wobbrock JO. ARTool: aligned rank transform for nonparametric factorial ANOVAs. R package version 0111. In: Proceedings of the ACM Conference on Human Factors in Computing Systems. ACM Press. 2021. https://github.com/mjskay/ARTool.
Bates D, Machler M, Bolker B, Walker S. Fitting linear mixed-effects models using {lme4}. J Statist Soft. 2015;67:1–48.
Kuczenski R, Segal DS. Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: comparison with amphetamine. J Neurochem. 1997;68:2032–2037.
Heal DJ, Smith SL, Gosden J, Nutt DJ. Amphetamine, past and present--a pharmacological and clinical perspective. J Psychopharmacol. 2013;27:479–496.
Scahill L, Carroll D, Burke KM. mechanism of action and clinical update. J Child Adolesc Psychiatr Nurs. 2004;17:85–86.
Shellenberg TP, Stoops WW, Lile JA, Rush CR. An update on the clinical pharmacology of methylphenidate: therapeutic efficacy, abuse potential and future considerations. Expert Rev Clin Pharmacol. 2020;13:825–833.
Chiu TH, Chen MJ, Yang YR, Yang JJ, Tang FI. Action of dexmedetomidine on rat locus coeruleus neurones: intracellular recording in vitro. Eur J Pharmacol. 1995;285:261–268.
Qiu G, Wu Y, Yang Z, et al. Dexmedetomidine activation of dopamine neurons in the ventral tegmental area attenuates the depth of sedation in mice. Anesthesiology. 2020;133:377–392.
Whittington RA, Virag L, Morishima HO, Vulliemoz Y. Dexmedetomidine decreases extracellular dopamine concentrations in the rat nucleus accumbens. Brain Res. 2001;919:132–138.
Whittington RA, Virag L. Dexmedetomidine-induced decreases in accumbal dopamine in the rat are partly mediated via the locus coeruleus. Anesth Analg. 2006;102:448–455.
Karhuvaara S, Kallio A, Salonen M, Tuominen J, Scheinin M. Rapid reversal of alpha 2-adrenoceptor agonist effects by atipamezole in human volunteers. Br J Clin Pharmacol. 1991;31:160–165.
Karhuvaara S, Kallio A, Scheinin M, Anttila M, Salonen JS, Scheinin H. Pharmacological effects and pharmacokinetics of atipamezole, a novel alpha 2-adrenoceptor antagonist—a randomized, double-blind cross-over study in healthy male volunteers. Br J Clin Pharmacol. 1990;30:97–106.
Scheinin H, Aantaa R, Anttila M, Hakola P, Helminen A, Karhuvaara S. Reversal of the sedative and sympatholytic effects of dexmedetomidine with a specific alpha2-adrenoceptor antagonist atipamezole: a pharmacodynamic and kinetic study in healthy volunteers. Anesthesiology. 1998;89:574–584.
Xie Z, Fox AP. Rapid emergence from dexmedetomidine sedation in Sprague Dawley rats by repurposing an alpha(2)-adrenergic receptor competitive antagonist in combination with caffeine. BMC Anesthesiol. 2023;23:39.
Paris A, Tonner PH. Dexmedetomidine in anaesthesia. Curr Opin Anaesthesiol. 2005;18:412–418.
Abdallah FW, Brull R. Facilitatory effects of perineural dexmedetomidine on neuraxial and peripheral nerve block: a systematic review and meta-analysis. Br J Anaesth. 2013;110:915–925.
Bellon M, Le Bot A, Michelet D, et al. Efficacy of intraoperative dexmedetomidine compared with placebo for postoperative pain management: a meta-analysis of published studies. Pain Ther. 2016;5:63–80.
Vaha-Vahe AT. The clinical effectiveness of atipamezole as a medetomidine antagonist in the dog. J Vet Pharmacol Ther. 1990;13:198–205.
Jang HS, Lee MG. Atipamezole changes the antinociceptive effects of butorphanol after medetomidine-ketamine anaesthesia in rats. Vet Anaesth Analg. 2009;36:591–596.
Natsheh JY, Shiflett MW. The effects of methylphenidate on goal-directed behavior in a rat model of ADHD. Front Behav Neurosci. 2015;9:326.
Carias E, Fricke D, Vijayashanthar A, et al. Weekday-only chronic oral methylphenidate self-administration in male rats: reversibility of the behavioral and physiological effects. Behav Brain Res. 2019;356:189–196.
Mashour GA. Top-down mechanisms of anesthetic-induced unconsciousness. Front Syst Neurosci. 2014;8:115.
Mashour GA, Hudetz AG. Bottom-up and top-down mechanisms of general anesthetics modulate different dimensions of consciousness. Front Neural Circuits. 2017;11:44.
Kokkinou M, Ashok AH, Howes OD. The effects of ketamine on dopaminergic function: meta-analysis and review of the implications for neuropsychiatric disorders. Mol Psychiatry. 2018;23:59–69.
Chen Y, Li S, Liang X, Zhang J. Differential alterations to the metabolic connectivity of the cortical and subcortical regions in rat brain during ketamine-induced unconsciousness. Anesth Analg. 2022;135:1106–1114.