Reduced immobilizing properties of isoflurane and nitrous oxide in mutant mice lacking the N-methyl-D-aspartate receptor GluR(epsilon)1 subunit are caused by the secondary effects of gene knockout.
BACKGROUND
Until recently, the N-methyl-D-aspartate (NMDA) receptor was considered to possibly mediate the immobility produced by inhaled anesthetics such as isoflurane and nitrous oxide. However, new evidence suggests that the role of this receptor in abolition of the movement response may be less important than previously thought. To provide further evidence supporting or challenging this view, we examined the anesthetic potencies of isoflurane and nitrous oxide in genetically modified animals with established NMDA receptor dysfunction caused by GluRepsilon1 subunit knockout.


METHODS
The immobilizing properties of inhaled anesthetics in mice quantitated by the minimum alveolar anesthetic concentration (MAC) were evaluated using the classic tail clamp method.


RESULTS
Compared with wild-type controls, NMDA receptor GluRepsilon1 subunit knockout mice displayed larger isoflurane MAC values indicating a resistance to the immobilizing action of isoflurane. Knockout mice were previously shown to have enhanced monoaminergic tone as a result of genetic manipulation, and this increase in MAC could be abolished in our experiments by pretreatment with the serotonin 5-hydroxytryptamine type 2A receptor antagonist ketanserin or with the dopamine D2 receptor antagonist droperidol at doses that did not affect MAC values in wild-type animals. Mutant mice also displayed resistance to the isoflurane MAC-sparing effect of nitrous oxide, but this resistance was similarly abolished by ketanserin and droperidol. Thus, resistance to the immobilizing action of inhaled anesthetics in knockout mice seems to be secondary to increased monoaminergic activation after knockout rather than a direct result of impaired NMDA receptor function.


CONCLUSIONS
Our results confirm recent findings indicating no critical contribution of NMDA receptors to the immobility induced by isoflurane and nitrous oxide. In addition, they demonstrate the ability of changes secondary to genetic manipulation to affect the results obtained in global knockout studies.
Petrenko
Andrey B
AB
Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi, Niigata 951-8510, Japan. abpetr@med.niigata-u.ac.j
Yamakura
Tomohiro
T
Kohno
Tatsuro
T
Sakimura
Kenji
K
Baba
Hiroshi
H
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004329:Droperidol / Q000494:pharmacology; D055786:Gene Knockout Techniques; D007530:Isoflurane / Q000493:pharmacokinetics / Q000494:pharmacology*; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009068:Movement / Q000187:drug effects*; D009609:Nitrous Oxide / Q000494:pharmacology*; D017288:Pain Threshold; D011650:Pulmonary Alveoli / Q000737:chemistry; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D012702:Serotonin Antagonists / Q000494:pharmacology
D018685:Anesthetics, Inhalation; D018492:Dopamine Antagonists; C120997:NR2A NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D012702:Serotonin Antagonists; D007650:Ketanserin; D007530:Isoflurane; D009609:Nitrous Oxide; D004329:Droperidol