Newly Published
Perioperative Medicine  |   December 2016
Ketamine Increases the Function of γ-Aminobutyric Acid Type A Receptors in Hippocampal and Cortical Neurons
Author Notes
  • From the Department of Physiology (D.-S.W., A.P., B.A.O.) and Anesthesia (B.A.O.), University of Toronto, Toronto, Ontario, Canada; Department of Anesthesia, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (B.A.O); and Department of Anaesthesia, Universidad de Chile, Santiago, Chile (A.P.).
  • Submitted for publication June 9, 2016. Accepted for publication November 14, 2016.
    Submitted for publication June 9, 2016. Accepted for publication November 14, 2016.×
  • Acknowledgments: The authors thank Ella Czerwinska, M.Sc., and Junhui Wang, M.D., Ph.D., Department of Physiology, University of Toronto, Toronto, Ontario, Canada, for their assistance with the cell cultures.
    Acknowledgments: The authors thank Ella Czerwinska, M.Sc., and Junhui Wang, M.D., Ph.D., Department of Physiology, University of Toronto, Toronto, Ontario, Canada, for their assistance with the cell cultures.×
  • Research Support: Supported by the Canadian Institutes of Health Research (CIHR; Ottawa, Ontario, Canada) to Dr. Orser (Open Operating Grants: 416838, 480143).
    Research Support: Supported by the Canadian Institutes of Health Research (CIHR; Ottawa, Ontario, Canada) to Dr. Orser (Open Operating Grants: 416838, 480143).×
  • Competing Interests: Dr. Penna was supported by a Fellowship Award from the Sleep and Biological Rhythms, a Canadian Institutes of Health Research Funded Research and Training Program, and by a Postdoctoral Fellowship Award from Becas Chile (Santiago, Region Metropolitana, Chile). The other authors declare no competing interests.
    Competing Interests: Dr. Penna was supported by a Fellowship Award from the Sleep and Biological Rhythms, a Canadian Institutes of Health Research Funded Research and Training Program, and by a Postdoctoral Fellowship Award from Becas Chile (Santiago, Region Metropolitana, Chile). The other authors declare no competing interests.×
  • Correspondence: Address correspondence to Dr. Orser: Department of Physiology, University of Toronto, Toronto, Ontario, M5S 1A8, Canada. beverley.orser@utoronto.ca. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Perioperative Medicine / Central and Peripheral Nervous Systems / Pharmacology
Perioperative Medicine   |   December 2016
Ketamine Increases the Function of γ-Aminobutyric Acid Type A Receptors in Hippocampal and Cortical Neurons
Anesthesiology Newly Published on December 15, 2016. doi:10.1097/ALN.0000000000001483
Anesthesiology Newly Published on December 15, 2016. doi:10.1097/ALN.0000000000001483
Abstract

Background: The “dissociative ” general anesthetic ketamine is a well-known N-methyl-d-aspartate receptor antagonist. However, whether ketamine, at clinically relevant concentrations, increases the activity of inhibitory γ-aminobutyric acid (GABA) receptor type A (GABAA) receptors in different brain regions remains controversial. Here, the authors studied the effects of ketamine on synaptic and extrasynaptic GABAA receptors in hippocampal neurons. Ketamine modulation of extrasynaptic GABAA receptors in cortical neurons was also examined.

Methods: Whole cell currents were recorded from cultured murine neurons. Current evoked by exogenous GABA, miniature inhibitory postsynaptic currents, and currents directly activated by ketamine were studied.

Results: Ketamine did not alter the amplitude, frequency, or kinetics of postsynaptic currents but increased a tonic inhibitory current generated by extrasynaptic GABAA receptors in hippocampal neurons. For example, ketamine (100 µM) increased the tonic current by 33.6 ± 6.5% (mean ± SEM; 95% CI, 18.2 to 48.9; n = 8, P < 0.001). Ketamine shifted the GABA concentration–response curve to the left, but only when GABAA receptors were activated by low concentrations of GABA (n = 6). The selective increase in tonic current was attributed to ketamine increasing the apparent potency of GABA at high-affinity extrasynaptic GABAA receptors. Ketamine also increased a tonic current in cortical neurons (n = 11). Ketamine directly gated the opening of GABAA receptors, but only at high concentrations that are unlikely to occur during clinical use.

Conclusions: Clinically relevant concentrations of ketamine increased the activity of high-affinity extrasynaptic GABAA receptors in the hippocampus and cortex, an effect that likely contributes to ketamine’s neurodepressive properties.