D-Amphetamine Rapidly Reverses Dexmedetomidine-Induced Unconsciousness in Rats

Risako Kato, Edlyn R Zhang, Olivia G Mallari, Olivia A Moody, Kathleen F Vincent, Eric D Melonakos, Morgan J Siegmann, Christa J Nehs, Timothy T Houle, Oluwaseun Akeju, Ken Solt, Risako Kato, Edlyn R Zhang, Olivia G Mallari, Olivia A Moody, Kathleen F Vincent, Eric D Melonakos, Morgan J Siegmann, Christa J Nehs, Timothy T Houle, Oluwaseun Akeju, Ken Solt

Abstract

D-amphetamine induces emergence from sevoflurane and propofol anesthesia in rats. Dexmedetomidine is an α2-adrenoreceptor agonist that is commonly used for procedural sedation, whereas ketamine is an anesthetic that acts primarily by inhibiting NMDA-type glutamate receptors. These drugs have different molecular mechanisms of action from propofol and volatile anesthetics that enhance inhibitory neurotransmission mediated by GABAA receptors. In this study, we tested the hypothesis that d-amphetamine accelerates recovery of consciousness after dexmedetomidine and ketamine. Sixteen rats (Eight males, eight females) were used in a randomized, blinded, crossover experimental design and all drugs were administered intravenously. Six additional rats with pre-implanted electrodes in the prefrontal cortex (PFC) were used to analyze changes in neurophysiology. After dexmedetomidine, d-amphetamine dramatically decreased mean time to emergence compared to saline (saline:112.8 ± 37.2 min; d-amphetamine:1.8 ± 0.6 min, p < 0.0001). This arousal effect was abolished by pre-administration of the D1/D5 dopamine receptor antagonist, SCH-23390. After ketamine, d-amphetamine did not significantly accelerate time to emergence compared to saline (saline:19.7 ± 18.0 min; d-amphetamine:20.3 ± 16.5 min, p = 1.00). Prefrontal cortex local field potential recordings revealed that d-amphetamine broadly decreased spectral power at frequencies <25 Hz and restored an awake-like pattern after dexmedetomidine. However, d-amphetamine did not produce significant spectral changes after ketamine. The duration of unconsciousness was significantly longer in females for both dexmedetomidine and ketamine. In conclusion, d-amphetamine rapidly restores consciousness following dexmedetomidine, but not ketamine. Dexmedetomidine reversal by d-amphetamine is inhibited by SCH-23390, suggesting that the arousal effect is mediated by D1 and/or D5 receptors. These findings suggest that d-amphetamine may be clinically useful as a reversal agent for dexmedetomidine.

Keywords: d-amphetamine; dexmedetomidine; emergence from anesthesia; ketamine; prefrontal cortex.

Conflict of interest statement

KS is a consultant to Takeda Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Kato, Zhang, Mallari, Moody, Vincent, Melonakos, Siegmann, Nehs, Houle, Akeju and Solt.

Figures

FIGURE 1
FIGURE 1
D-amphetamine accelerates recovery from unconsciousness induced by dexmedetomidine, but not ketamine. (A) Time course of the behavioral experiments with dexmedetomidine. The onset of the second drug infusion is set as time = 0. (B) Box-whisker plot of the time to emergence in all 16 rats after dexmedetomidine (50 μg/kg), followed by the listed drugs (plus sign = mean time to emergence, filled circle = individual data point). (C) Time course of the behavioral experiments with ketamine. The onset of the second drug infusion is set as time = 0. (D) Box-whisker plot of the time to emergence in all 16 rats after ketamine (50 mg/kg), followed by the listed drugs (***p < 0.001; Bonferroni post-hoc comparison; N.S. = not significantly different).
FIGURE 2
FIGURE 2
Female rats are more sensitive to dexmedetomidine- and ketamine-induced unconsciousness than males. (A) Box-whisker plot of the time to emergence in male (blue) and female (magenta) rats after dexmedetomidine (50 μg/kg), followed by the listed drugs (plus signs = mean time to emergence, filled circle = individual data point). (B) Box-whisker plot of the time to emergence after ketamine (50 mg/kg), followed by the listed drugs (*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, Bonferroni post-hoc comparison; N.S. = not significant; blue asterisk = comparison between males, magenta asterisk = comparison between females, black asterisk = between male and female comparison).
FIGURE 3
FIGURE 3
D-amphetamine restores awake-like neurophysiology in the PFC after dexmedetomidine. (A) Experimental time courses, spectrograms, and EMG recordings from a representative rat. The arrow indicates ROR. (B) Raw LFP waveforms from each time period. (C) The median and 95% CI of power spectral density during awake (black), post-LOC (red), and 10 min after saline or d-amphetamine (blue).
FIGURE 4
FIGURE 4
D-amphetamine does not appreciably alter the spectral content of PFC LFP recordings after ketamine. (A) Experimental time courses, spectrograms, and EMG recordings from a representative rat. The arrows indicate ROR. (B) Raw LFP waveforms from each time period. (C) The median and 95% CI of spectral density during awake (black), post-LOR (red), and 10 min after saline or d-amphetamine (blue).

References

    1. Akeju O., Hobbs L. E., Gao L., Burns S. M., Pavone K. J., Plummer G. S., et al. (2018). Dexmedetomidine Promotes Biomimetic Non-rapid Eye Movement Stage 3 Sleep in Humans: A Pilot Study. Clin. Neurophysiol. 129, 69–78. 10.1016/j.clinph.2017.10.005
    1. Akeju O., Kim S.-E., Vazquez R., Rhee J., Pavone K. J., Hobbs L. E., et al. (2016). Spatiotemporal Dynamics of Dexmedetomidine-Induced Electroencephalogram Oscillations. PLoS One 11, e0163431. 10.1371/journal.pone.0163431
    1. Akeju O., Pavone K. J., Westover M. B., Vazquez R., Prerau M. J., Harrell P. G., et al. (2014). A Comparison of Propofol- and Dexmedetomidine-Induced Electroencephalogram Dynamics Using Spectral and Coherence Analysis. Anesthesiology 121, 978–989. 10.1097/aln.0000000000000419
    1. Becker J. B. (1990). Direct Effect of 17?-estradiol on Striatum: Sex Differences in Dopamine Release. Synapse 5, 157–164. 10.1002/syn.890050211
    1. Bol Cjjg C., Danhof M., Stanski D. R., Mandema J. W. (1997). Pharmacokinetic-pharmacodynamic Characterization of the Cardiovascular, Hypnotic, EEG and Ventilatory Responses to Dexmedetomidine in the Rat. J. Pharmacol. Exp. Ther. 283, 1051–1058.
    1. Brown C., Deiner S. (2016). Perioperative Cognitive Protection. Br. J. Anaesth. 117, iii52–iii61. 10.1093/bja/aew361
    1. Brown E. N., Purdon P. L., Van Dort C. J. (2011). General Anesthesia and Altered States of Arousal: a Systems Neuroscience Analysis. Annu. Rev. Neurosci. 34, 601–628. 10.1146/annurev-neuro-060909-153200
    1. Buchanan F. F., Myles P. S., Cicuttini F. (2009). Patient Sex and its Influence on General Anaesthesia. Anaesth. Intensive Care 37, 207–218. 10.1177/0310057x0903700201
    1. Buchanan F. F., Myles P. S., Leslie K., Forbes A., Cicuttini F. (2006). Gender and Recovery after General Anesthesia Combined with Neuromuscular Blocking Drugs. Anesth. Analgesia 102, 291–297. 10.1213/01.Ane.0000181321.55422.C6
    1. Di Paolo T., Falardeau P., Morissette M. (1988). Striatal D-2 Dopamine Agonist Binding Sites Fluctuate during the Rat Estrous Cycle. Life Sci. 43, 665–672. 10.1016/0024-3205(88)90137-3
    1. Di Paolo T., Rouillard C., Bédard P. (1985). 17β-estradiol at a Physiological Dose Acutely Increases Dopamine Turnover in Rat Brain. Eur. J. Pharmacol. 117, 197–203. 10.1016/0014-2999(85)90604-1
    1. Fasting S., Gisvold S. E. (2002). Serious Intraoperative Problems - a Five-Year Review of 83,844 Anesthetics. Can. J. Anesth/j Can. Anesth. 49, 545–553. 10.1007/bf03017379
    1. Flükiger J., Hollinger A., Speich B., Meier V., Tontsch J., Zehnder T., et al. (2018). Dexmedetomidine in Prevention and Treatment of Postoperative and Intensive Care Unit Delirium: a Systematic Review and Meta-Analysis. Ann. Intensive Care 8, 92. 10.1186/s13613-018-0437-z
    1. Fong R., Wang L., Zacny J. P., Khokhar S., Apfelbaum J. L., Fox A. P., et al. (2018). Caffeine Accelerates Emergence from Isoflurane Anesthesia in Humans. Anesthesiology 129, 912–920. 10.1097/aln.0000000000002367
    1. Gan T. J., Glass P. S., Sigl J., Sebel P., Payne F., Rosow C., et al. (1999). Women Emerge from General Anesthesia with Propofol/Alfentanil/Nitrous Oxide Faster Than Men. Anesthesiology 90, 1283–1287. 10.1097/00000542-199905000-00010
    1. Hambrecht-Wiedbusch V. S., Li D., Mashour G. A. (2017). Paradoxical Emergence. Anesthesiology 126, 482–494. 10.1097/aln.0000000000001512
    1. Heal D. J., Cheetham S. C., Smith S. L. (2009). The Neuropharmacology of ADHD Drugs In Vivo: Insights on Efficacy and Safety. Neuropharmacology 57, 608–618. 10.1016/j.neuropharm.2009.08.020
    1. Hemmings H. C., Jr., Riegelhaupt P. M., Kelz M. B., Solt K., Eckenhoff R. G., Orser B. A., et al. (2019). Towards a Comprehensive Understanding of Anesthetic Mechanisms of Action: A Decade of Discovery. Trends Pharmacol. Sci. 40, 464–481. 10.1016/j.tips.2019.05.001
    1. Hiyoshi T., Kambe D., Karasawa J., Chaki S. (2014). Involvement of Glutamatergic and GABAergic Transmission in MK-801-Increased Gamma Band Oscillation Power in Rat Cortical Electroencephalograms. Neuroscience 280, 262–274. 10.1016/j.neuroscience.2014.08.047
    1. Ho K. K., Flood P. (2004). Single Amino Acid Residue in the Extracellular Portion of Transmembrane Segment 2 in the Nicotinic α7 Acetylcholine Receptor Modulates Sensitivity to Ketamine. Anesthesiology 100, 657–662. 10.1097/00000542-200403000-00028
    1. Hoover W. B., Vertes R. P. (2007). Anatomical Analysis of Afferent Projections to the Medial Prefrontal Cortex in the Rat. Brain Struct. Funct. 212, 149–179. 10.1007/s00429-007-0150-4
    1. Hunter J. C., Fontana D. J., Hedley L. R., Jasper J. R., Lewis R., Link R. E., et al. (1997). Assessment of the Role of α2 -adrenoceptor Subtypes in the Antinociceptive, Sedative and Hypothermic Action of Dexmedetomidine in Transgenic Mice. Br. J. Pharmacol. 122, 1339–1344. 10.1038/sj.bjp.0701520
    1. Kelz M. B., García P. S., Mashour G. A., Solt K. (2019). Escape from Oblivion. Anesth. Analgesia 128, 726–736. 10.1213/ane.0000000000004006
    1. Kelz M. B., Sun Y., Chen J., Cheng Meng Q., Moore J. T., Veasey S. C., et al. (2008). An Essential Role for Orexins in Emergence from General Anesthesia. Proc. Natl. Acad. Sci. 105, 1309–1314. 10.1073/pnas.0707146105
    1. Kenny J. D., Taylor N. E., Brown E. N., Solt K. (2015). Dextroamphetamine (But Not Atomoxetine) Induces Reanimation from General Anesthesia: Implications for the Roles of Dopamine and Norepinephrine in Active Emergence. PLoS One 10, e0131914. 10.1371/journal.pone.0131914
    1. Kilkenny C., Browne W., Cuthill I. C., Emerson M., Altman D. G., Group N. C. R. R. G. W. (2010). Animal Research: Reporting In Vivo Experiments: the ARRIVE Guidelines. Br. J. Pharmacol. 160, 1577–1579. 10.1111/j.1476-5381.2010.00872.x
    1. Kubota T., Anzawa N., Hirota K., Yoshida H., Kushikata T., Matsuki A. (1999). Effects of Ketamine and Pentobarbital on Noradrenaline Release from the Medial Prefrontal Cortex in Rats. Can. J. Anesth/j Can. Anesth. 46, 388–392. 10.1007/bf03013235
    1. Kuhn C. M., Schanberg S. M. (1978). Metabolism of Amphetamine after Acute and Chronic Administration to the Rat. J. Pharmacol. Exp. Ther. 207, 544–554.
    1. Kushikata T., Yoshida H., Kudo M., Kudo T., Kudo T., Hirota K. (2011). Role of Coerulean Noradrenergic Neurones in General Anaesthesia in Rats. Br. J. Anaesth. 107, 924–929. 10.1093/bja/aer303
    1. Lakhlani P. P., Macmillan L. B., Guo T. Z., Mccool B. A., Lovinger D. M., Maze M., et al. (1997). Substitution of a Mutant 2a-Adrenergic Receptor via "hit and Run" Gene Targeting Reveals the Role of This Subtype in Sedative, Analgesic, and Anesthetic-Sparing Responses In Vivo. Proc. Natl. Acad. Sci. 94, 9950–9955. 10.1073/pnas.94.18.9950
    1. Li D., Hambrecht-Wiedbusch V. S., Mashour G. A. (2017). Accelerated Recovery of Consciousness after General Anesthesia Is Associated with Increased Functional Brain Connectivity in the High-Gamma Bandwidth. Front. Syst. Neurosci. 11, 16. 10.3389/fnsys.2017.00016
    1. Li J., Li H., Wang D., Guo Y., Zhang X., Ran M., et al. (2019). Orexin Activated Emergence from Isoflurane Anaesthesia Involves Excitation of Ventral Tegmental Area Dopaminergic Neurones in Rats. Br. J. Anaesth. 123, 497–505. 10.1016/j.bja.2019.07.005
    1. Lorrain D. S., Baccei C. S., Bristow L. J., Anderson J. J., Varney M. A. (2003). Effects of Ketamine and N-Methyl-D-Aspartate on Glutamate and Dopamine Release in the Rat Prefrontal Cortex: Modulation by a Group II Selective Metabotropic Glutamate Receptor Agonist LY379268. Neuroscience 117, 697–706. 10.1016/s0306-4522(02)00652-8
    1. Ma Y., Miracca G., Yu X., Harding E. C., Miao A., Yustos R., et al. (2019). Galanin Neurons Unite Sleep Homeostasis and α2-Adrenergic Sedation. Curr. Biol. 29, 3315–3322. 10.1016/j.cub.2019.07.087
    1. Macdonald E., Scheinin M., Scheinin H., Virtanen R. (1991). Comparison of the Behavioral and Neurochemical Effects of the Two Optical Enantiomers of Medetomidine, a Selective Alpha-2-Adrenoceptor Agonist. J. Pharmacol. Exp. Ther. 259, 848–854.
    1. Mantz J., Josserand J., Hamada S. (2011). Dexmedetomidine: New Insights. Eur. J. Anaesthesiology 28, 3–6. 10.1097/EJA.0b013e32833e266d
    1. Mason K. P. (2017). Paediatric Emergence Delirium: a Comprehensive Review and Interpretation of the Literature. Br. J. Anaesth. 118, 335–343. 10.1093/bja/aew477
    1. Meuret P., Backman S. B., Bonhomme V., Plourde G., Fiset P. (2000). Physostigmine Reverses Propofol-Induced Unconsciousness and Attenuation of the Auditory Steady State Response and Bispectral Index in Human Volunteers. Anesthesiology 93, 708–717. 10.1097/00000542-200009000-00020
    1. Mitra P., Bokil H. (2008). Observed Brain Dynamics. Oxford ; New York: Oxford University Press.
    1. Miyazaki M., Kadoi Y., Saito S. (2009). Effects of Landiolol, a Short-Acting Beta-1 Blocker, on Hemodynamic Variables during Emergence from Anesthesia and Tracheal Extubation in Elderly Patients with and without Hypertension. J. Anesth. 23, 483–488. 10.1007/s00540-009-0805-9
    1. Moghaddam B., Adams B., Verma A., Daly D. (1997). Activation of Glutamatergic Neurotransmission by Ketamine: a Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex. J. Neurosci. 17, 2921–2927. 10.1523/jneurosci.17-08-02921.1997
    1. Moody O. A., Zhang E. R., Arora V., Kato R., Cotten J. F., Solt K. (2020). D-amphetamine Accelerates Recovery of Consciousness and Respiratory Drive after High-Dose Fentanyl in Rats. Front. Pharmacol. 11, 585356. 10.3389/fphar.2020.585356
    1. Morissette M., Di Paolo T. (1993). Sex and Estrous Cycle Variations of Rat Striatal Dopamine Uptake Sites. Neuroendocrinology 58, 16–22. 10.1159/000126507
    1. Myles P. S., Mcleod A. D., Hunt J. O., Fletcher H. (2001). Sex Differences in Speed of Emergence and Quality of Recovery after Anaesthesia: Cohort Study. BMJ 322, 710–711. 10.1136/bmj.322.7288.710
    1. Nelson L. E., Lu J., Guo T., Saper C. B., Franks N. P., Maze M. (2003). The α2-Adrenoceptor Agonist Dexmedetomidine Converges on an Endogenous Sleep-Promoting Pathway to Exert its Sedative Effects. Anesthesiology 98, 428–436. 10.1097/00000542-200302000-00024
    1. Orser B. A., Pennefather P. S., Macdonald J. F. (1997). Multiple Mechanisms of Ketamine Blockade of N-Methyl-D-Aspartate Receptors. Anesthesiology 86, 903–917. 10.1097/00000542-199704000-00021
    1. Pal D., Dean J. G., Liu T., Li D., Watson C. J., Hudetz A. G., et al. (2018). Differential Role of Prefrontal and Parietal Cortices in Controlling Level of Consciousness. Curr. Biol. 28, 2145–2152. 10.1016/j.cub.2018.05.025
    1. Pertovaara A., Haapalinna A., Sirviö J., Virtanen R. (2005). Pharmacological Properties, Central Nervous System Effects, and Potential Therapeutic Applications of Atipamezole, a Selective α2-Adrenoceptor Antagonist. CNS Drug Rev. 11, 273–288. 10.1111/j.1527-3458.2005.tb00047.x
    1. Robinson T. N., Raeburn C. D., Tran Z. V., Angles E. M., Brenner L. A., Moss M. (2009). Postoperative Delirium in the Elderly. Ann. Surg. 249, 173–178. 10.1097/SLA.0b013e31818e4776
    1. Saland S. K., Kabbaj M. (2018). Sex Differences in the Pharmacokinetics of Low-Dose Ketamine in Plasma and Brain of Male and Female Rats. J. Pharmacol. Exp. Ther. 367, 393–404. 10.1124/jpet.118.251652
    1. Scheinin H., Aantaa R., Anttila M., Hakola P., Helminen A., Karhuvaara S. (1998). Reversal of the Sedative and Sympatholytic Effects of Dexmedetomidine with a Specific α2-Adrenoceptor Antagonist Atipamezole. Anesthesiology 89, 574–584. 10.1097/00000542-199809000-00005
    1. Soldin O. P., Mattison D. R. (2009). Sex Differences in Pharmacokinetics and Pharmacodynamics. Clin. Pharmacokinet. 48, 143–157. 10.2165/00003088-200948030-00001
    1. Solt K., Van Dort C. J., Chemali J. J., Taylor N. E., Kenny J. D., Brown E. N. (2014). Electrical Stimulation of the Ventral Tegmental Area Induces Reanimation from General Anesthesia. Anesthesiology 121, 311–319. 10.1097/aln.0000000000000117
    1. Taylor N. E., Chemali J. J., Brown E. N., Solt K. (2013). Activation of D1 Dopamine Receptors Induces Emergence from Isoflurane General Anesthesia. Anesthesiology 118, 30–39. 10.1097/ALN.0b013e318278c896
    1. Taylor N. E., Van Dort C. J., Kenny J. D., Pei J., Guidera J. A., Vlasov K. Y., et al. (2016). Optogenetic Activation of Dopamine Neurons in the Ventral Tegmental Area Induces Reanimation from General Anesthesia. Proc. Natl. Acad. Sci. USA 113, 12826–12831. 10.1073/pnas.1614340113
    1. Tzabazis A., Miller C., Dobrow M. F., Zheng K., Brock-Utne J. G. (2015). Delayed Emergence after Anesthesia. J. Clin. Anesth. 27, 353–360. 10.1016/j.jclinane.2015.03.023
    1. Wang Q., Fong R., Mason P., Fox A. P., Xie Z. (2014). Caffeine Accelerates Recovery from General Anesthesia. J. Neurophysiol. 111, 1331–1340. 10.1152/jn.00792.2013
    1. Zhang L.-N., Li Z.-J., Tong L., Guo C., Niu J.-Y., Hou W.-G., et al. (2012). Orexin-A Facilitates Emergence from Propofol Anesthesia in the Rat. Anesth. Analgesia 115, 789–796. 10.1213/ANE.0b013e3182645ea3
    1. Zhang Z., Ferretti V., Güntan İ., Moro A., Steinberg E. A., Ye Z., et al. (2015). Neuronal Ensembles Sufficient for Recovery Sleep and the Sedative Actions of α2 Adrenergic Agonists. Nat. Neurosci. 18, 553–561. 10.1038/nn.3957
    1. Zhou C., Douglas J. E., Kumar N. N., Shu S., Bayliss D. A., Chen X. (2013). Forebrain HCN1 Channels Contribute to Hypnotic Actions of Ketamine. Anesthesiology 118, 785–795. 10.1097/ALN.0b013e318287b7c8
    1. Zhou W., Cheung K., Kyu S., Wang L., Guan Z., Kurien P. A., et al. (2018). Activation of Orexin System Facilitates Anesthesia Emergence and Pain Control. Proc. Natl. Acad. Sci. USA 115, E10740–e10747. 10.1073/pnas.1808622115

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren