title: Possible role of GABAergic depolarization in neocortical neurons in generating hyperexcitatory behaviors during emergence from sevoflurane anesthesia in the rat.
abstract: Hyperexcitatory behaviors occurring after sevoflurane anesthesia are of serious clinical concern, but the underlying mechanism is unknown. These behaviors may result from the potentiation by sevoflurane of GABAergic depolarization/excitation in neocortical neurons, cells implicated in the genesis of consciousness and arousal. The current study sought to provide evidence for this hypothesis with rats, the neocortical neurons of which are known to respond to GABA (γ-aminobutyric acid) with depolarization/excitation at early stages of development (i.e., until the second postnatal week) and with hyperpolarization/inhibition during adulthood. Employing behavioral tests and electrophysiological recordings in neocortical slice preparations, we found: (1) sevoflurane produced PAHBs (post-anesthetic hyperexcitatory behaviors) in postnatal day (P)1-15 rats, whereas it failed to elicit PAHBs in P16 or older rats; (2) GABAergic PSPs (postsynaptic potentials) were depolarizing/excitatory in the neocortical neurons of P5 and P10 rats, whereas mostly hyperpolarizing/inhibitory in the cells of adult rats; (3) at P14-15, <50% of rats had PAHBs and, in general, the cells of the animals with PAHBs exhibited strongly depolarizing GABAergic PSPs, whereas those without PAHBs showed hyperpolarizing or weakly depolarizing GABAergic PSPs; (4) bumetanide [inhibitor of the Cl- importer NKCC (Na+-K+-2Cl- cotransporter)] treatment at P5 suppressed PAHBs and depolarizing GABAergic responses; and (5) sevoflurane at 1% (i.e., concentration<1 minimum alveolar concentration) potentiated depolarizing GABAergic PSPs in the neurons of P5 and P10 rats and of P14-15 animals with PAHBs, evoking action potentials in ≥50% of these cells. On the basis of these results, we conclude that sevoflurane may produce PAHBs by potentiating GABAergic depolarization/excitation in neocortical neurons.
authors.affiliation: *Department of Anesthesiology and Pain Medicine, Korea University College of Medicine, Guro Hospital, 148 Gurodong-ro, Guro-gu, Seoul, Korea.
authors.forename: Byung-Gun
authors.initials: BG
authors.lastname: Lim
authors.affiliation: †Department of Anesthesiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 20092, China.
authors.forename: Feng-Yan
authors.initials: FY
authors.lastname: Shen
authors.affiliation: ‡Department of Physiology and Neuroscience Research Institute, Korea University College of Medicine, 126-1 Anam-dong 5-ga, Seoul, Korea.
authors.forename: Young-Beom
authors.initials: YB
authors.lastname: Kim
authors.affiliation: ‡Department of Physiology and Neuroscience Research Institute, Korea University College of Medicine, 126-1 Anam-dong 5-ga, Seoul, Korea.
authors.forename: Woong Bin
authors.initials: WB
authors.lastname: Kim
authors.affiliation: ‡Department of Physiology and Neuroscience Research Institute, Korea University College of Medicine, 126-1 Anam-dong 5-ga, Seoul, Korea.
authors.forename: Yoon Sik
authors.initials: YS
authors.lastname: Kim
authors.affiliation: ‡Department of Physiology and Neuroscience Research Institute, Korea University College of Medicine, 126-1 Anam-dong 5-ga, Seoul, Korea.
authors.forename: Hee Chul
authors.initials: HC
authors.lastname: Han
authors.affiliation: *Department of Anesthesiology and Pain Medicine, Korea University College of Medicine, Guro Hospital, 148 Gurodong-ro, Guro-gu, Seoul, Korea.
authors.forename: Mi-Kyoung
authors.initials: MK
authors.lastname: Lee
authors.affiliation: *Department of Anesthesiology and Pain Medicine, Korea University College of Medicine, Guro Hospital, 148 Gurodong-ro, Guro-gu, Seoul, Korea.
authors.forename: Myoung-Hoon
authors.initials: MH
authors.lastname: Kong
authors.affiliation: ‡Department of Physiology and Neuroscience Research Institute, Korea University College of Medicine, 126-1 Anam-dong 5-ga, Seoul, Korea.
authors.forename: Yang In
authors.initials: YI
authors.lastname: Kim
mesh_terms: D000367:Age Factors; D017109:Akathisia, Drug-Induced / Q000503:physiopathology*; D018685:Anesthetics, Inhalation / Q000009:adverse effects*; D018686:Anesthetics, Intravenous / Q000009:adverse effects; D000818:Animals; D002034:Bumetanide / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008738:Methyl Ethers / Q000009:adverse effects*; D019579:Neocortex / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D015742:Propofol / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D000077149:Sevoflurane; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology; D055366:Synaptic Potentials / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D008738:Methyl Ethers; D011963:Receptors, GABA-A; D049994:Sodium Potassium Chloride Symporter Inhibitors; D002034:Bumetanide; D000077149:Sevoflurane; D005680:gamma-Aminobutyric Acid; D015742:Propofol