Halothane depresses glutamatergic neurotransmission to brain stem inspiratory premotor neurons in a decerebrate dog model. Anesthesiology 2003 Apr;98(4):897-905
Date
03/27/2003Pubmed ID
12657851DOI
10.1097/00000542-200304000-00016Scopus ID
2-s2.0-0037381082 (requires institutional sign-in at Scopus site) 12 CitationsAbstract
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.
CONCLUSION: 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.
Author List
Stucke AG, Zuperku EJ, Tonkovic-Capin V, Tonkovic-Capin M, Hopp FA, Kampine JP, Stuth EAAuthors
Astrid G. Stucke MD Professor in the Anesthesiology department at Medical College of WisconsinEckehard A. Stuth MD Professor in the Anesthesiology department at Medical College of Wisconsin
Edward J. Zuperku PhD Professor in the Anesthesiology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Anesthetics, InhalationAnimals
Bicuculline
Brain Stem
Decerebrate State
Dogs
Dose-Response Relationship, Drug
Electrophysiology
Excitatory Amino Acid Agonists
Excitatory Postsynaptic Potentials
GABA Antagonists
Glutamic Acid
Halothane
Motor Neurons
N-Methylaspartate
Oxygen
Patch-Clamp Techniques
Receptors, AMPA
Receptors, Glutamate
Receptors, N-Methyl-D-Aspartate
Synaptic Transmission