Nature Neuroscience5, 979 - 984 (2002)
Published online: 26 August 2002; | doi:10.1038/nn913
The sedative component of anesthesia is mediated by GABAA receptors in an endogenous sleep pathway
L. E. Nelson1, 2, T. Z. Guo1, J. Lu3, C. B. Saper3, N. P. Franks1, 2
& M. Maze1, 2
1
Department of Anaesthetics & Intensive Care, Chelsea & Westminster Hospital, Imperial College School of Medicine, London SW10 9NH, UK
2
Biophysics Section, Blackett Laboratory, Department of Biological Sciences, Imperial College of Science, Technology & Medicine, London SW7 2BW, UK
3
Department of Neurology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA
Correspondence should be addressed to N. P. Franks n.franks@ic.ac.uk
We investigated the role of regionally discrete GABA (-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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-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.
