GABAA-R α4 subunits are required for the low dose locomotor stimulatory effect of alphaxalone, but not for several other behavioral responses to alphaxalone, etomidate or propofol.
γ-Aminobutyric acid type A receptors (GABAA-Rs) are considered to be the primary molecular targets of injectable anesthetics such as propofol, etomidate and the neurosteriod, alphaxalone. A number of studies have sought to understand the specific GABAA-R subtypes involved in the mechanism of action of these three drugs. Here, we investigated the role of α4-subunit containing GABAA-Rs in the neurobehavioral responses to these drugs. Drug responses in α4 subunit knockout (KO) mice were compared to wild type (WT) littermate controls. While etomidate and propofol are currently used as injectable anesthetics, alphaxalone belongs to the class of neurosteroid drugs having anesthetic effects. Low dose effects of etomidate and alphaxalone were studied using an open field assay. The moderate and high dose effects of all three anesthetics were measured using the rotarod and loss of righting reflex assays, respectively. The locomotor stimulatory effect of alphaxalone was reduced significantly in α4 KO mice compared to WT controls. Neither the low dose sedating effect of etomidate, nor the moderate/high dose effect of any of the drugs differed between genotypes. These results suggest that α4 subunit-containing GABAA-Rs are required for the low dose, locomotor stimulatory effect of alphaxalone but are not required for the sedating effect of etomidate or the moderate/high dose effects of etomidate, propofol or alphaxalone on motor ataxia and loss of righting reflex.
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
Sangeetha V
SV
Iyer
Dave
D
Chandra
Gregg E
GE
Homanics
D000777:Anesthetics / Q000008:administration & dosage*; D000818:Animals; D005045:Etomidate / Q000008:administration & dosage*; D005260:Female; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D011277:Pregnanediones / Q000008:administration & dosage*; D015742:Propofol / Q000008:administration & dosage*; D021122:Protein Subunits / Q000172:deficiency; D011963:Receptors, GABA-A / Q000172:deficiency*
D000777:Anesthetics; C546261:Gabra4 protein, mouse; D011277:Pregnanediones; D021122:Protein Subunits; D011963:Receptors, GABA-A; C006477:alphaxalone; D015742:Propofol; D005045:Etomidate