Effects of halothane on excitatory neurotransmission to medullary expiratory neurons in a decerebrate dog model.
BACKGROUND
The activity of canine expiratory (E) neurons in the caudal ventral respiratory group is primarily dependent on N-methyl-D-aspartic acid (NMDA) receptor-mediated excitatory chemodrive inputs and modulated by an inhibitory mechanism mediated via gamma-aminobutyric acidA (GABA(A)) receptors. In an intact canine preparation, halothane depressed the activity of these neurons mainly by reduction in overall glutamatergic excitation. A new decerebrate preparation allows comparison of the effects of halothane on these synaptic mechanisms with an anesthetic-free baseline state.


METHODS
Two separate studies were performed in decerebrate, vagotomized, paralyzed, mechanically ventilated dogs during hypercapnic hyperoxia. In study 1, the effect of 1 minimum alveolar concentration (MAC) halothane on extracellularly recorded E neuronal activity was studied before and during complete GABA(A) receptor blockade by localized pressure ejection of bicuculline. Complete blockade of the inhibitory mechanism allowed differentiation between the effects of halothane on overall GABA(A)-mediated inhibition and on overall NMDA receptor-mediated excitation. In study 2, the effect of 1 MAC halothane on the dose response of neurons to localized picoejection of the glutamate agonist NMDA was used to estimate halothane effect on postsynaptic glutamatergic excitatory neurotransmission.


RESULTS
In study 1, the spontaneous activity of 14 E neurons was depressed 38.6 +/- 20.6% (mean +/- SD) by 1 MAC halothane. Overall excitation was depressed 31.5 +/- 15.5%. The GABAergic inhibition showed a 11.7 +/- 18.3% enhancement during halothane. In study 2, the spontaneous activity of 13 E neurons was again significantly depressed by 1 MAC halothane (27.9 +/- 10.6%), but the postsynaptic response of the neurons to exogenous NMDA was not significantly depressed by halothane (3.3 +/- 38.4%).


CONCLUSIONS
Together these results suggest that in our E neuron paradigm, halothane exerted its depressive effect mainly via reduction of glutamatergic presynaptic mechanisms.
Stuth
E A
EA
Medical College of Wisconsin, Children's Hospital of Wisconsin, and the Zablocki Veterans Administration Medical Center, Milwaukee 53295, USA.
Krolo
M
M
Stucke
A G
AG
Tonkovic-Capin
M
M
Tonkovic-Capin
V
V
Hopp
F A
FA
Kampine
J P
JP
Zuperku
E J
EJ
D018685:Anesthetics, Inhalation / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001640:Bicuculline / Q000031:analogs & derivatives* / Q000494:pharmacology; D003655:Decerebrate State / Q000503:physiopathology*; D004285:Dogs; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006221:Halothane / Q000378:metabolism / Q000494:pharmacology*; D023421:Models, Animal; D016202:N-Methylaspartate / Q000494:pharmacology; D010791:Phrenic Nerve / Q000187:drug effects; D011650:Pulmonary Alveoli / Q000378:metabolism; D012119:Respiration / Q000187:drug effects; D012125:Respiratory Center / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
D018685:Anesthetics, Inhalation; D018690:Excitatory Amino Acid Agonists; D018756:GABA Antagonists; D016202:N-Methylaspartate; C006749:bicuculline methochloride; D006221:Halothane; D001640:Bicuculline