Brain and Behavior. 2018;8:e00990.
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1 | INTRODUCTION
General anesthesia is a medically induced state of unconsciousness
with loss of protective reflexes and alternations of neurotransmit-
ters, resulting from the administration of one or more general anes-
thetic agents (Jevtovic- Todorovic, 2016). Ketamine, a phencyclidine
derivative agent, is widely used as a short- acting “dissociative” gen-
eral anesthetic (Li & Vlisides, 2016). Although ketamine is classically
considered a noncompetitive N- methyl- D- aspartate (NMDA) re-
ceptor antagonist, it is actually a wide- ranging pleiotropic molecule
that affects a variety of receptors and cellular processes. Ketamine
blocks nicotinic acetylcholine ion channels, increases dopaminergic
Aquaporin- 4 knockout mice exhibit increased hypnotic
susceptibility to ketamine
* | Wangshu Dai
* | Ai Ge
* | Yi Fan
| Gang Hu
| Yinming Zeng
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.
*These authors contributed equally to this work.
[Correction added on 1 June 2018, after first online publication: Yunluo Lv’s affiliation has been updated.]
Department of Anesthesiology, Nanjing
The Comprehensive Cancer Centre of Drum
Department of Respiratory Medicine, Tongji
Jiangsu Key Laboratory of
Neurodegeneration, Department of
Jiangsu Province Institute of
Yunluo Lv, Department of Anesthesiology,
Yinming Zeng, Jiangsu Province Institute of
China (No. 81001428) and Jiangsu Province
Purpose: This study examines anesthetic/hypnotic effects of ketamine in AQP4
knockout (KO) and wild- type (WT) mice with the particular focus on
Materials and Methods: Ketamine (100 mg/kg) was intraperitoneally injected in 16
WT and 16 KO mice. The hypnotic potencies were evaluated by the loss of the right-
ing reflex (LORR). The amino acids neurotransmitter levels in prefrontal cortex were
measured by microdialysis.
Results: This study demonstrated that AQP4 knockout significantly shortened the
latency compared with WT mice (98.0 ± 4.2 vs. 138.1 ± 15.0 s, p < .05) and pro-
longed duration of LORR (884.7 ± 58.6 vs. 562.0 ± 51.7 s, p < .05) compared with
WT mice in LORR induced by ketamine. Microdialysis showed that lack of AQP4
markedly decreased glutamate level within 20 min (p < .05) and increased γ-
aminobutyric acid (GABA) level within 30–40 min (p < .05) after use of ketamine.
Moreover, the levels of taurine were remarkably higher in KO mice than in WT mice,
but no obvious differences in aspartate were observed between two genotypes.
Conclusion: AQP4 deficiency led to more susceptibility of mice to ketamine, which is
probably due to the modulation of specific neurotransmitters, hinting an essential
maintenance of synaptic activity mediated by AQP4 in the action of ketamine.
aquaporin-4, ketamine, loss of the righting reflex, microdialysis, synaptic transmission