title: Isoflurane abolishes spontaneous firing of serotonin neurons and masks their pH/CO₂ chemosensitivity.
abstract: Serotonin (5-hydroxytryptamine, 5-HT) neurons from the mouse and rat rostral medulla are stimulated by increased CO2 when studied in culture or brain slices. However, the response of 5-HT neurons has been variable when animals are exposed to hypercapnia in vivo. Here we examined whether halogenated inhalational anesthetics, which activate TWIK-related acid-sensitive K(+) (TASK) channels, could mask an effect of CO2 on 5-HT neurons. During in vivo plethysmography in mice, isoflurane (1%) markedly reduced the hypercapnic ventilatory response (HCVR) by 78-96% depending upon mouse strain and ambient temperature. In a perfused rat brain stem preparation, isoflurane (1%) reduced or silenced spontaneous firing of medullary 5-HT neurons in situ and abolished their responses to elevated perfusate Pco2. In dissociated cell cultures, isoflurane (1%) hyperpolarized 5-HT neurons by 6.52 ± 3.94 mV and inhibited spontaneous firing. A subsequent decrease in pH from 7.4 to 7.2 depolarized neurons by 4.07 ± 2.10 mV, but that was insufficient to reach threshold for firing. Depolarizing current restored baseline firing and the firing frequency response to acidosis, indicating that isoflurane did not block the underlying mechanisms mediating chemosensitivity. These results demonstrate that isoflurane masks 5-HT neuron chemosensitivity in vitro and in situ and markedly decreases the HCVR in vivo. The use of this class of anesthetic has a particularly potent inhibitory effect on chemosensitivity of 5-HT neurons.
authors.affiliation: Interdisciplinary Graduate Program in Neuroscience, University of Iowa Hospitals and Clinics, Iowa City, Iowa; Department of Neurology and NIH/NINDS Center for SUDEP Research, University of Iowa Hospitals and Clinics, Iowa City, Iowa; cory-massey@uiowa.edu.
authors.forename: Cory A
authors.initials: CA
authors.lastname: Massey
authors.affiliation: Department of Biology and Wildlife, University of Alaska, Fairbanks, Alaska;
authors.forename: Kimberly E
authors.initials: KE
authors.lastname: Iceman
authors.affiliation: Department of Biology and Wildlife, University of Alaska, Fairbanks, Alaska;
authors.forename: Sara L
authors.initials: SL
authors.lastname: Johansen
authors.affiliation: Department of Neurology and NIH/NINDS Center for SUDEP Research, University of Iowa Hospitals and Clinics, Iowa City, Iowa;
authors.forename: Yuanming
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Biology and Wildlife, University of Alaska, Fairbanks, Alaska; Institute of Arctic Biology, University of Alaska, Fairbanks, Alaska;
authors.forename: Michael B
authors.initials: MB
authors.lastname: Harris
authors.affiliation: Department of Neurology and NIH/NINDS Center for SUDEP Research, University of Iowa Hospitals and Clinics, Iowa City, Iowa; Department of Molecular Physiology and Biophysics, University of Iowa Hospitals and Clinics, Iowa City, Iowa; and Department of Veterans Affairs Medical Center, Iowa City, Iowa.
authors.forename: George B
authors.initials: GB
authors.lastname: Richerson
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D018685:Anesthetics, Inhalation / Q000008:administration & dosage; D000818:Animals; D002245:Carbon Dioxide / Q000008:administration & dosage*; D002478:Cells, Cultured; D002628:Chemoreceptor Cells / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D006863:Hydrogen-Ion Concentration; D007530:Isoflurane / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D059326:Serotonergic Neurons / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*
chemical_list: D018685:Anesthetics, Inhalation; D002245:Carbon Dioxide; D007530:Isoflurane
keywords: TASK; anesthesia; breathing; chemoreceptor; raphe