title: Halothane depresses glutamatergic neurotransmission to brain stem inspiratory premotor neurons in a decerebrate dog model.
abstract: BACKGROUND
  Inspiratory bulbospinal neurons in the caudal ventral medulla are premotor neurons that drive phrenic motoneurons and ultimately the diaphragm. Excitatory drive to these neurons is mediated by N-methyl-d-aspartate (NMDA) receptors and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors and modulated by an inhibitory gamma-aminobutyric acid(A) (GABA(A))ergic input. The authors investigated the effect of halothane on these synaptic mechanisms in decerebrate dogs.
  
  
  METHODS
  Studies were performed in decerebrate, vagotomized, paralyzed, and mechanically ventilated dogs during hypercapnic hyperoxia. The effect of 1 minimum alveolar concentration (MAC) halothane on extracellularly recorded neuronal activity was measured during localized picoejection of the GABA(A) receptor blocker bicuculline and the glutamate agonists AMPA and NMDA. Complete blockade of the GABA(A)ergic mechanism by bicuculline allowed differentiation between the effects of halothane on overall GABA(A)ergic inhibition and on overall glutamatergic excitation. The neuronal responses to exogenous AMPA and NMDA were used to estimate the anesthetic effect on postsynaptic glutamatergic neurotransmission.
  
  
  RESULTS
  Halothane, 1 MAC, depressed the spontaneous activity of 21 inspiratory neurons by 20.6 +/- 18.0% (mean +/- SD; P = 0.012). Overall glutamatergic excitation was depressed 15.4 +/- 20.2% (P = 0.001), while overall GABA(A)ergic inhibition did not change. The postsynaptic responses to exogenous AMPA and NMDA were also depressed by 18.6 +/- 35.7% (P = 0.03) and 22.2 +/- 26.2% (P = 0.004), respectively.
  
  
  CONCLUSIONS
  Halothane, 1 MAC, depressed the activity of inspiratory premotor neurons by a reduction of glutamatergic excitation. Overall inhibitory drive did not change. The postsynaptic AMPA and NMDA receptor response was significantly reduced. These findings contrast with studies in expiratory premotor neurons in which overall inhibition was significantly increased by halothane and there was no reduction in the postsynaptic glutamate receptor response.
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, and the Zablocki VA Medical Center, Milwaukee, WI 53295, USA.
authors.forename: Astrid G
authors.initials: AG
authors.lastname: Stucke
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Zuperku
authors.forename: Viseslav
authors.initials: V
authors.lastname: Tonkovic-Capin
authors.forename: Mislav
authors.initials: M
authors.lastname: Tonkovic-Capin
authors.forename: Francis A
authors.initials: FA
authors.lastname: Hopp
authors.forename: John P
authors.initials: JP
authors.lastname: Kampine
authors.forename: Eckehard A E
authors.initials: EA
authors.lastname: Stuth
mesh_terms: D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D001933:Brain Stem / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D003655:Decerebrate State / Q000503:physiopathology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018756:GABA Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000502:physiology*; D006221:Halothane / Q000494:pharmacology*; D009046:Motor Neurons / Q000187:drug effects*; D016202:N-Methylaspartate / Q000494:pharmacology; D010100:Oxygen / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D018091:Receptors, AMPA / Q000187:drug effects; D017470:Receptors, Glutamate / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D018685:Anesthetics, Inhalation; D018690:Excitatory Amino Acid Agonists; D018756:GABA Antagonists; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D016202:N-Methylaspartate; D010100:Oxygen; D006221:Halothane; D001640:Bicuculline