ANESTHESIA SENSITIVITY IN MICE THAT LACK THE BETA-3 SUBUNIT OF THE GAMMA-AMINOBUTYRIC-ACID TYPE-A RECEPTOR

Background: The mammalian gamma-aminobutyric acid type A (GABA(A)) rec eptor, a Likely target of anesthetic action, exhibits remarkable subun it heterogeneity, In vitro expression studies suggest that there is su bunit specificity to anesthetic responses at the GABA(A) receptor, The authors tested whether genetically engineered mice that lack the beta 3 subunit of the GABA(A) receptor differed in their sensitivities to several general anesthetic agents. Methods: Median effective concentra tions for loss-of-righting reflex and tail clamp/withdrawal for enflur ane and halothane were determined in mice with and without the beta 3 gene and gene product. Sleep time was measured after intraperitoneal i njection of pentobarbital, ethanol, etomidate, and midazolam. Results: Null allele mice (beta 3 -/-) did not differ from wildtype mice (beta 3 +/+) in the obtunding response to enflurane and halothane but were significantly more resistant to enflurane (null allele half-effect con centrations [EC50] of 2.59 +/- 0.10 us. wild-type EC50 of 2.06 +/- 0.1 2 atm %, P < 0.001) and halothane (null allele EC50 of 1.73 +/- 0.04 v s. wild-type EC50 of 1.59 +/- 0.05 atm %, P = 0.01) as determined by t ail clamp response. Wild-type and null allele mice exhibited divergent responses to other sedative agents active at the GABA(A) receptor. No differences were noted in sleep times after administration of pentoba rbital and ethanol, but null allele mice were more resistant to etomid ate (null allele EC50 of 17.8 +/- 1.9 min vs. mild-type EC50 of 26.2 /- 2.4 min, P < 0.02) and midazolam (null allele EC50 of 14.2 +/- 7.8 min us. wild-type EC50 of 41.3 +/- 10.4 min, P < 0.05). Conclusions: T he beta 3 subunit of the GABA(A) receptor appears to be important in t he mediation of the immobilizing (tail clamp) but not obtunding (loss- of-righting reflex) effects of the volatile anesthetic agents enfluran e and halothane, These data support the hypotheses that separate compo nents of the anesthetic state are mediated via different central nervo us system loci; that the GABA(A) receptor is a likely target for the i mmobilizing response to volatile anesthetic agents; and that the beta 3 subunit plays a direct or indirect role in the mediation of this res ponse. Absence of the beta 3 subunit appears to attenuate the obtundin g effect of midazolam and etomidate but appears not to alter the obtun ding effect of pentobarbital, enflurane, and halothane, suggesting tha t these anesthetic agents produce hypnosis by different specific molec ular mechanisms.