Deletion of GABAA receptor alpha 1 subunit-containing receptors alters responses to ethanol and other anesthetics.
GABA(A) receptors have been implicated in mediating several acute effects of ethanol including anxiolysis, ataxia, sedation/hypnosis, and anticonvulsant activity. Ethanol sensitivity of neurons has been associated with expression of alpha1 subunit-containing receptors. The objective of this study was to determine the contribution of alpha1 subunit containing receptors to ethanol responses in comparison to neurosteroids and other anesthetics using GABA(A) receptor alpha1 subunit knockout mice. Deletion of alpha1 subunit-containing receptors did not alter the anxiolytic, ataxic, anticonvulsant, or hypnotic effects of ethanol or acute functional tolerance to ethanol but did increase sensitivity to the locomotor-stimulating effects of ethanol. The ability of ethanol to potentiate muscimol-stimulated chloride uptake and ethanol clearance was also not altered following alpha1 subunit deletion. The anticonvulsant and hypnotic effects of neurosteroids as well as their potentiating effect on GABA-mediated Cl(-) uptake were unaltered in alpha1(-/-) mice. The hypnotic effect of pentobarbital, etomidate, and midazolam were reduced, whereas the effect of ketamine was enhanced in alpha1(-/-) mice. Thus, GABA(A) receptor alpha1 subunit-containing receptors appear to influence the motor-stimulating effect of ethanol and the sedative/hypnotic effects of some anesthetics, but not ethanol. These receptors do not appear to be necessary for most ethanol responses, suggesting involvement of other GABA(A) receptor subtypes or other targets altogether.
Kralic
J E
JE
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Wheeler
M
M
Renzi
K
K
Ferguson
C
C
O'Buckley
T K
TK
Grobin
A C
AC
Morrow
A L
AL
Homanics
G E
GE
D000777:Anesthetics / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001007:Anxiety / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects*; D001640:Bicuculline / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000378:metabolism / Q000494:pharmacology*; D002712:Chlorides / Q000378:metabolism; D003900:Desoxycorticosterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D004361:Drug Tolerance; D000431:Ethanol / Q000378:metabolism / Q000494:pharmacology*; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009118:Muscimol / Q000494:pharmacology; D004856:Postural Balance / Q000187:drug effects; D011280:Pregnanolone / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000235:genetics / Q000502:physiology*; D013256:Steroids / Q000378:metabolism / Q000494:pharmacology
D000777:Anesthetics; D002492:Central Nervous System Depressants; D002712:Chlorides; D018755:GABA Agonists; D018756:GABA Antagonists; C546241:Gabra1 protein, mouse; D011963:Receptors, GABA-A; D013256:Steroids; D009118:Muscimol; D000431:Ethanol; D003900:Desoxycorticosterone; C009413:tetrahydrodeoxycorticosterone; D011280:Pregnanolone; D001640:Bicuculline