GENE KNOCKOUT OF THE ALPHA-6 SUBUNIT OF THE GAMMA-AMINOBUTYRIC-ACID TYPE-A RECEPTOR - LACK OF EFFECT ON RESPONSES TO ETHANOL, PENTOBARBITAL, AND GENERAL-ANESTHETICS
Ge. Homanics et al., GENE KNOCKOUT OF THE ALPHA-6 SUBUNIT OF THE GAMMA-AMINOBUTYRIC-ACID TYPE-A RECEPTOR - LACK OF EFFECT ON RESPONSES TO ETHANOL, PENTOBARBITAL, AND GENERAL-ANESTHETICS, Molecular pharmacology, 51(4), 1997, pp. 588-596
The alpha 6 subunit of the gamma-aminobutyric acid type A receptor (GA
BA(A)-R) has been implicated in mediating the intoxicating effects of
ethanol and the motor ataxic effects of general anesthetics. To test t
his hypothesis, we used gene targeting in embryonic stem cells to crea
te mice lacking a functional alpha 6 gene. Homozygous mice are viable
and fertile and have grossly normal cerebellar cytoarchitecture. North
ern blot and reverse transcriptase-polymerase chain reaction analyses
demonstrated thai the targeting event disrupted production oi function
al alpha 6 mRNA. Autoradiography of histological sections of adult bra
ins demonstrated that diazepam-insensitive binding of [H-3]Ro15-4513 t
o the cerebellar granule cell layer of wild-type mice was completely a
bsent in homozygous mice. Cerebellar GABA(A)-R density was unchanged i
n the mutant mice; however, the apparent affinity for muscimol was mar
kedly reduced. Sleep time response to injection of ethanol after pretr
eatment with vehicle or Ro15-4513 did not differ between genotypes. Sl
eep time response to injection of pentobarbital and loss of righting r
eflex and response to tail clamp stimulus in mice anesthetized with vo
latile anesthetics also did not differ between genotypes. Thus, the al
pha 6 subunit of the GABA(A)-R is not required far normal development,
viability, and fertility and does not seem to be a critical or unique
component of the neuronal pathway mediating the hypnotic effect of et
hanol and its antagonism by Ro15-4513 in mice. Similarly, the alpha 6
subunit does not seem to be involved in the behavioral responses to ge
neral anesthetics or pentobarbital.