INCREASED SENSITIVITY TO PENTOBARBITAL BUT NOT VOLATILE ANESTHETICS IN GLUR2 DEFICIENT MICE*

Abstract

S349 INTRODUCTION: Compared to wildtype littermates, mice genetically engineered to lack the GluR2 subunit of the AMPA receptor (GluR2 KO) demonstrate a decreased time to loss of righting reflex (LORR) and increased duration of LORR from barbiturate administration [1]. We hypothesized that if volatile anesthetics and barbiturates have similar mechanisms of action, then GluR2 KO mice would also demonstrate an enhanced sensitivity to volatile agents. To test this notion, we measured the MAC of isoflurane, desflurane, and halothane in GluR2 KO mice. METHODS: Age- and sex-matched GluR2 KO and wildtype littermate mice (12 per group, total 24 mice) were retained in clear plastic cylinders and initially received isoflurane at 0.6%, desflurane at 5.6%, or halothane at 0.9% given in oxygen. Rectal temperature was maintained between 36 to 39 [degree sign] C. Anesthetic concentrations were increased in 20 % increments after 20 min equilibration at each concentration. At the end of each equilibration period, movement in response to a 1 min tail-clamp stimulus was assessed. The MAC for each mouse was recorded and compared between GluR2 KO and wildtype mice using the Student's t-test. RESULTS: Neither isoflurane, desflurane, nor halothane MAC differed between GluR2 KO and wildtype mice. Isoflurane MAC was 1.30 +/- 0.28 % (mean +/- SD) and 1.25 +/- 0.24 % in the wildtype and GluR2KO mice, respectively (p=0.62). Values for desflurane were 8.00 +/- 0.84 % and 7.76 +/- 0.92 %, respectively (p=0.54), and for halothane were 1.17 +/- 0.09 % and 1.25 +/- 0.09 %, respectively (p=0.09). (Figure 1)Figure 1CONCLUSIONS: In contrast to the differential effect of pentobarbital on the righting reflex in GluR2 KO mice versus wildtype mice, MAC for isoflurane, desflurane, and halothane did not differ for the two strains. These results suggest that different mechanisms may underlie the effects of these two classes of depressant drugs. Alternatively, the presence of the GluR2 subunit may influence neuronal networks that mediate the righting reflex but not the withdrawal to tail-clamp. ACKNOWLEDGMENTS: This work was supported by the First IARS Frontiers in Anesthesia Research Award to BAO, by the CAS/MRC Fellowship and PSIF grant to DTI, and by a grant to EIE from the NIH. BAO is also supported by the Ontario Ministry of Health.