Alcohol (ethanol) is widely consumed for its desirable effects but unfortunately has strong addiction potential. Some imidazobenzodiazepines such as Ro15-4513 are able to antagonize many ethanol-induced behaviors. Controversial biochemical and pharmacological evidence suggest that the effects of these ethanol antagonists and ethanol are mediated specifically via overlapping binding sites on α4/δ-containing GABAA-Rs. To investigate the requirement of α4-containing GABAA-Rs in the mechanism of action of Ro15-4513 on behavior, wildtype (WT) and α4 knockout (KO) mice were compared for antagonism of ethanol-induced motor incoordination and hypnosis. Motor effects of ethanol were tested in two different fixed speed rotarod assays. In the first experiment, mice were injected with 2.0 g/kg ethanol followed 5 min later by 10 mg/kg Ro15-4513 (or vehicle) and tested on a rotarod at 8 rpm. In the second experiment, mice received a single injection of 1.5 g/kg ethanol ± 3 mg/kg Ro15-4513 and were tested on a rotarod at 12 rpm. In both experiments, the robust Ro15-4513 antagonism of ethanol-induced motor ataxia that was observed in WT mice was absent in KO mice. A loss of righting reflex (LORR) assay was used to test Ro15-4513 (20 mg/kg) antagonism of ethanol (3.5 g/kg)-induced hypnosis. An effect of sex was observed on the LORR assay, so males and females were analyzed separately. In male mice, Ro15-4513 markedly reduced ethanol-induced LORR in WT controls, but α4 KO mice were insensitive to this effect of Ro15-4513. In contrast, female KO mice did not differ from WT controls in the antagonistic effects of Ro15-4513 on ethanol-induced LORR. We conclude that Ro15-4513 requires α4-containing receptors for antagonism of ethanol-induced LORR (in males) and motor ataxia.
Keywords: alcohol, alcohol antagonist, alcohol receptor, benzodiazepine, extrasynaptic GABAA receptor, Ro15-4513
Citation: Iyer SV, Benavides RA, Chandra D, Cook JM, Rallapalli S, June HL and Homanics GE (2011) α4-Containing GABAA receptors are required for antagonism of ethanol-induced motor incoordination and hypnosis by the imidazobenzodiazepine Ro15-4513. Front. Pharmacol. 2:18. doi: 10.3389/fphar.2011.00018
Received: 04 November 2010;
Accepted: 21 March 2011;
Published online: 04 April 2011.
Edited by:A. Leslie Morrow, University of North Carolina School of Medicine, USA
Reviewed by:Esa R. Korpi, University of Helsinki, Finland
Copyright: © 2011 Iyer, Benavides, Chandra, Cook, Rallapalli, June and Homanics. This is an open-access article subject to a non-exclusive license between the authors and Frontiers Media SA, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and other Frontiers conditions are complied with.
*Correspondence: Gregg E. Homanics, Department of Anesthesiology, University of Pittsburgh, Room 6060 Biomedical Science Tower-3, 3501 Fifth Avenue, Pittsburgh, PA 15261, USA.e-mail: firstname.lastname@example.org