Blockade of Brain γ-Aminobutyric Acid a Receptors Antagonizes Hypnotic Action of Isoflurane in Rats―GABA Receptor and Isoflurane Induced Hypnosis
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Abstract
Although in vitro studies have demonstrated that isoflurane potentiates the function of γ-aminobutyric acid A receptors (GABAARs), the in vivo data are controversial. To determine if GABAARs contribute to the loss-of righting reflex (LORR) induced by isoflurane, we studied the LORR in the absence and presence of gabazine, a competitive GABAAR antagonist, in Sprague-Dawley rats anesthetized with either isoflurane or ketamine. Administration of isoflurane and ketamine induced LORR in a dose-dependent manner. Gabazine significantly antagonized the effect of isoflurane and shifted the dose response curve to the right. In addition, gabazine prolonged the onset time of LORR induced by isoflurane. Ketamine induced LORR was not affected by gabazine. This indicates that centrally administered gabazine selectively blocks the effect of isoflurane, and the effect of gabazine is not due to a non-specific CNS excitatory action. These results suggest that the hypnotic effect of isoflurane is at least in part mediated by GABAARs.
- U. Rudolph and B. Antkowiak, “Molecular and Neuronal Substrates for General Anaesthetics,” Nature Reviews Neuroscience, Vol. 5, No. 9, 2004, pp. 709-720. Hdoi:10.1038/nrn1496
- L. E. Nelson, T. Z. Guo, J. Lu, C. B. Saper, N. P. Franks and M. Maze, “The Sedative Component of Anesthesia Is Mediated by GABA(A) Receptors in an Endogenous Sleep Pathway,” Nature Neuroscience, Vol. 5, No. 10, 2002, pp. 979-984. Hdoi:10.1038/nn913
- G. Vanini, C. J. Watson, R. Lydic and H. A. Baghdoyan, “Gamma-Aminobutyric Acid-Mediated Neurotransmission in the Pontine Reticular Formation Modulates Hypnosis, Immobility, and Breathing during Isoflurane Anesthesia,” Anesthesiology, Vol. 109, No. 6, 2008, pp. 978- 988. Hdoi:10.1097/ALN.0b013e31818e3b1b
- B. J. Saab, A. J. Maclean, M. Kanisek, A. A. Zurek, L. J. Martin, J. C. Roder and B. A. Orser, “Short-Term Memory Impairment after Isoflurane in Mice Is Prevented by the Alpha5 Gamma-Aminobutyric Acid Type A Receptor Inverse Agonist L-655,708,” Anesthesiology, Vol. 113, No. 5, pp. 1061-1071. Hdoi:10.1097/ALN.0b013e3181f56228
- M. Sugimura, S. Kitayama, K. Morita, Y. Imai, M. Irifune, T. Takarada, M. Kawahara and T. Dohi, “Effects of GABAergic Agents on Anesthesia Induced by Halothane, Isoflurane, and Thiamylal in Mice,” Pharmacology Biochemistry and Behavior, Vol. 72, No. 1-2, 2002, pp. 111- 116. Hdoi:10.1016/S0091-3057(01)00728-6
- G. Paxinos and C. Watson, “The Rat Brain in Stereotaxic Coordinates,” 6th Edition, Academic Press, Cambridge, 2007.
- D. R. Waud, “On Biological Assays Involving Quantal Responses,” Journal of Pharmacology and Experimental Therapeutics, Vol. 183, No. 3, 1972, pp. 577-607.
- N. P. Franks, “General Anaesthesia: From Molecular Targets to Neuronal Pathways of Sleep and Arousal,” Nature Reviews Neuroscience, Vol. 9, No. 5, 2008, pp. 370-386. Hdoi:10.1038/nrn2372
- N. P. Franks and W. R. Lieb, “Molecular and Cellular Mechanisms of General Anaesthesia,” Nature, Vol. 367, 1994, pp. 607-614. Hdoi:10.1038/367607a0
- D. Lodge, N. A. Anis and N. R. Burton, “Effects of Optical Isomers of Ketamine on Excitation of Cat and Rat Spinal Neurones by Amino-Acids and Acetylcholine,” Neuroscience Letters, Vol. 29, No. 3, 1982, pp. 281-286. Hdoi:10.1016/0304-3940(82)90330-5
- S. Ueno, J. Bracamontes, C. Zorumski, D. S. Weiss and J. H. Steinbach, “Bicuculline and Gabazine Are Allosteric Inhibitors of Channel Opening of the GABAA Receptor,” The Journal of Neuroscience, Vol. 17, No. 2, 1997, pp. 625-634.