Halothane and diazepam inhibit ketamine-induced c-fos expression in the rat cingulate cortex.
BACKGROUND
Ketamine, a noncompetitive N-methyl-D-aspartate antagonist, has psychotomimetic side effects. Recent studies have shown that noncompetitive N-methyl-D-aspartate antagonists cause morphologic damage to the cingulate and retrosplenial cortices and induce c-fos protein (c-Fos) in the same regions. Although benzodiazepines are effective in preventing these side effects, the neural basis of the drug interactions has not been established.


METHODS
The effects of diazepam and halothane on c-Fos expression induced by ketamine were studied. Diazepam (1 and 5 mg/kg) or vehicle were administered subcutaneously, followed 7 min later by 100 mg/kg ketamine given intraperitoneally. Halothane (1.0 and 1.8%), was administered continuously from 10 min before ketamine administration until brain fixation. Two hours after ketamine injection, rats were perfused and their brains fixed and extracted. Brain sections were prepared in a cryostat and c-Fos expression was detected using immunohistochemical methods.


RESULTS
Ketamine induced c-Fos-like immunoreactivity in the cingulate and retrosplenial cortices, thalamus, and neocortex. Diazepam suppressed the ketamine-induced c-Fos-like immunoreactivity in the cingulate and retrosplenial cortices in a dose-dependent manner, leaving the thalamus and neocortex less affected. Halothane suppressed the ketamine-induced c-Fos-like immunoreactivity in the cingulate and retrosplenial cortices and the neocortex in a dose-dependent manner, leaving the thalamus relatively unaffected.


CONCLUSIONS
Halothane and diazepam inhibited ketamine-induced c-Fos expression in the cingulate and retrosplenial cortices, leaving the thalamus relatively unaffected.
Nakao
S
S
Department of Critical Care Medicine, Kyoto University Hospital, Japan.
Adachi
T
T
Murakawa
M
M
Shinomura
T
T
Kurata
J
J
Shichino
T
T
Shibata
M
M
Tocyama
I
I
Kimura
H
H
Mori
K
K
D018685:Anesthetics, Inhalation / Q000494:pharmacology; D000818:Animals; D003975:Diazepam / Q000494:pharmacology*; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects*; D006179:Gyrus Cinguli / Q000187:drug effects* / Q000378:metabolism; D006221:Halothane / Q000494:pharmacology*; D007150:Immunohistochemistry; D007649:Ketamine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008297:Male; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar
D018685:Anesthetics, Inhalation; D018691:Excitatory Amino Acid Antagonists; D018757:GABA Modulators; D016202:N-Methylaspartate; D007649:Ketamine; D003975:Diazepam; D006221:Halothane