Faster emergence behavior from ketamine/xylazine anesthesia with atipamezole versus yohimbine

• Type of Material: Article
• Authors: Lukas Mees, Atlanta VA Medical Center; Jonathan Fidler, Atlanta VA Medical Center; Matthias Kreuzer, Atlanta VA Medical Center; Jieming Fu, Atlanta VA Medical Center; Machelle Pardue, Emory University; Paul Garcia, Emory University
• Language: English
• Date: 2018-10-29
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © Public Library of Science. All rights reserved.
• License: Creative Commons Creative Commons CC0 1.0 Universal
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0199087
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 13
• Issue: 10
• Start Page: e0199087
• End Page: e0199087
• Grant/Funding Information: Dr. García’s research efforts are supported in part by a Career Development Award #BX00167 (PI: PS García, MD, PhD) from the United States Department of Veteran Affairs (https://www.research.va.gov/funding/), Biomedical Laboratory Research and Development Service (https://www.research.va.gov/services/blrd/) and the James S. McDonnell Foundation grant #220023046 (PI: PS García, MD, PhD) (https://www.jsmf.org/apply/).; The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; Dr. Pardue’s research efforts are supported by a Research Scientist Award C9257-5 from the Department of Veterans Affairs, Rehabilitation Research and Development Service (http://www.rehab.research.va.gov/).
• Keywords: DEXMEDETOMIDINE; XYLAZINE; ALPHA(1); Science & Technology; KETAMINE; RECOVERY; ANTAGONISM; Multidisciplinary Sciences; Science & Technology - Other Topics; RECEPTORS; MICE; AGENT; RATS
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Recent interest in reversal of the hypnotic effects of anesthesia has mainly focused on overcoming a surge in GABA-mediated inhibitory signaling through activation of subcortical arousal circuits or antagonizing GABA receptors. Here we examine the reversal of anesthesia produced from non-GABA agents ketamine/xylazine and the effects of antagonists of adrenoreceptors. These antagonists vary in selectivity and produce temporally unique waking behavior post-anesthesia. We compared two antagonists with differential selectivity for α1- vs. α2-receptors, yohimbine (YOH, 1:40 selectivity) and atipamezole (ATI, 1:8500). Adult mice received intraperitoneal injections of either YOH (4.3 mg/kg), ATI (0.4 mg/kg), or saline after achieving sustained loss of righting following injection of ketamine/xylazine (ketamine: 65.0 mg/kg; xylazine: 9.9 mg/kg). Behaviors indicative of the post-anesthesia, re-animation sequence were carefully monitored and the timing of each behavior relative to anesthesia induction was compared. Both YOH and ATI hastened behaviors indicative of emergence, but ATI was faster than YOH to produce certain behaviors, including whisker movement (YOH: 21.9±1.5 min, ATI: 17.5±0.5 min, p = 0.004) and return of righting reflex (RORR) (YOH: 40.6±8.8 min, ATI: 26.0±1.2 min, p<0.001). Interestingly, although YOH administration hastened early behavioral markers of emergence relative to saline (whisking), the completion of the emergence sequence (time from first marker to appearance of RORR) was delayed with YOH. We attribute this effect to antagonism of α1 receptors by yohimbine. Also notable was the failure of either antagonist to hasten the re-establishment of coordinated motor behavior (e.g., attempts to remove adhesive tape on the forepaw placed during anesthesia) relative to the end of emergence (RORR). In total, our work suggests that in addition to pharmacokinetic effects, re-establishment of normal waking behaviors after anesthesia involves neuronal circuits dependent on time and/or activity.