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The sedative component of anesthesia is mediated by GABAA receptors in an endogenous sleep pathway

Nature Neuroscience volume 5, pages 979–984 (2002)Cite this article

Abstract

We investigated the role of regionally discrete GABA (γ-aminobutyric acid) receptors in the sedative response to pharmacological agents that act on GABAA receptors (muscimol, propofol and pentobarbital; 'GABAergic agents') and to ketamine, a general anesthetic that does not affect GABAA receptors. Behavioral studies in rats showed that the sedative response to centrally administered GABAergic agents was attenuated by the GABAA receptor antagonist gabazine (systemically administered). The sedative response to ketamine, by contrast, was unaffected by gabazine. Using c-Fos as a marker of neuronal activation, we identified a possible role for the tuberomammillary nucleus (TMN): when gabazine was microinjected directly into the TMN, it attenuated the sedative response to GABAergic agents. Furthermore, the GABAA receptor agonist muscimol produced a dose-dependent sedation when it was administered into the TMN. We conclude that the TMN is a discrete neural locus that has a key role in the sedative response to GABAergic anesthetics.

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Figure 1: Simplified NREM sleep-promoting pathway.
Figure 2: Systemic gabazine attenuates sedation induced by GABAergic agents but not by NMDA receptor–mediated agents.
Figure 3: c-Fos expression induced by GABAergic agents.
Figure 4: Effects of discrete injections of GABAA receptor agonist and antagonist into the TMN.

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Acknowledgements

The Medical Research Council (UK; G9817980 and G9100635), the Westminster Medical Trust (UK) and the National Institutes of Health (USA; HL60292 and AG09975) supported this work.

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Authors and Affiliations

  1. Department of Anaesthetics & Intensive Care, Chelsea & Westminster Hospital, Imperial College School of Medicine, London, SW10 9NH, UK

    L. E. Nelson, T. Z. Guo, N. P. Franks & M. Maze

  2. Department of Biological Sciences, Biophysics Section, Blackett Laboratory, Imperial College of Science, Technology & Medicine, London, SW7 2BW, UK

    L. E. Nelson, N. P. Franks & M. Maze

  3. Department of Neurology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, 02215, Massachusetts, USA

    J. Lu & C. B. Saper

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  1. L. E. Nelson
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Correspondence to N. P. Franks.

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Nelson, L., Guo, T., Lu, J. et al. The sedative component of anesthesia is mediated by GABAA receptors in an endogenous sleep pathway. Nat Neurosci 5, 979–984 (2002). https://doi.org/10.1038/nn913

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