Modeling the GABAergic action of etomidate on the thalamocortical system.
BACKGROUND
We have used a computational model of the thalamocortical system to investigate the effects of a GABAergic anesthetic (etomidate) on cerebral cortical and thalamic neuronal function. We examined the effects of phasic and tonic inhibition, as well as the relative importance of anesthetic action in the thalamus and cortex.


METHODS
The amount of phasic GABAergic inhibition was adjusted in the model to simulate etomidate concentrations of between 0.25 and 2 microM, with the concentration range producing unconsciousness assumed to be between 0.25 and 0.5 microM. In addition, we modeled tonic inhibition separately, and then phasic and tonic inhibition together. We also introduced phasic and tonic inhibition into the cerebral cortex and thalamus separately to determine the relative importance of each of these structures to anesthetic-induced depression of the thalamocortical system.


RESULTS
Phasic inhibition decreased cortical neuronal firing by 11%-18% in the 0.25-0.5 microM range and by 38% at 2 microM. Tonic inhibition produced similar depression (11%-21%) in the 0.25-0.5 microM range but 65% depression at 2 microM; phasic and tonic inhibition combined produced the most inhibition (76% depression at 2 microM). When the thalamus and cortex were separately subjected to phasic and tonic inhibition, cortical firing rates decreased less compared to when both structures were targeted. In the 0.25-0.5 microM range, cortical firing rate was minimally affected when etomidate action was simulated in the thalamus only.


CONCLUSIONS
This computational model of the thalamocortical system indicated that tonic GABAergic inhibition seems to be more important than phasic GABAergic inhibition (especially at larger etomidate concentrations), although both combined had the most effect on cerebral cortical firing rates. Furthermore, etomidate action in the thalamus, by itself, does not likely explain etomidate-induced unconsciousness.
Talavera
Jason A
JA
Department of Anesthesiology and Pain Medicine, University of California, Davis, CA 95616, USA.
Esser
Steven K
SK
Amzica
Florin
F
Hill
Sean
S
Antognini
Joseph F
JF
D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D005045:Etomidate / Q000494:pharmacology*; D006801:Humans; D008959:Models, Neurological; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D013788:Thalamus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014793:Visual Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018686:Anesthetics, Intravenous; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D005045:Etomidate