Original Research ARTICLE
Ro 15-4513 antagonizes alcohol-induced sedation in mice through αβγ2-type GABAA receptors
- 1 Pharmacology, Institute of Biomedicine, University of Helsinki, Helsinki, Finland
- 2 Department of Psychiatry and Psychotherapy, University Medical Centre, Johannes Gutenberg University Mainz, Mainz, Germany
- 3 Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK
- 4 Division of Cell and Molecular Biology, Imperial College London, London, UK
Ethyl alcohol (ethanol) has many molecular targets in the nervous system, its potency at these sites being low compared to those of sedative drugs. This has made it difficult to discover ethanol’s binding site(s). There are two putative binding sites at γ-aminobutyric acid (GABA) type A receptor subtypes for the proposed ethanol antagonist Ro 15-4513, the established γ2 subunit-dependent benzodiazepine site and the recently reported δ subunit-dependent Ro 15-4513/ethanol binding site. Here, we aimed at clarifying the in vivo role of Ro 15-4513 at these two sites. We found that the antagonism of ethanol actions by Ro 15-4513 in wildtype mice was dependent on the test: an open field test showed that light sedation induced by 1.5–1.8 g/kg ethanol was sensitive to Ro 15-4513, whereas several tests for ethanol-induced anxiolytic effects showed that the ethanol-induced effects were insensitive to Ro 15-4513. Antagonism of ethanol-induced sedation by Ro 15-4513 was unaffected in GABAA receptor δ subunit knockout mice. By contrast, when testing the GABAA receptor γ2 subunit F77I knock-in mouse line (γ2I77 mice) with its strongly reduced affinity of the benzodiazepine sites for Ro 15-4513, we found that the ethanol-induced sedation was no longer antagonized by Ro 15-4513. Indeed, γ2I77 mice had only a small proportion of high-affinity binding of [3H]Ro 15-4513 left as compared to wildtype mice, especially in the caudate–putamen and septal areas, but these residual sites are apparently not involved in ethanol antagonism. In conclusion, we found that Ro 15-4513 abolished the sedative effect of ethanol by an action on γ2 subunit-dependent benzodiazepine sites.
Keywords: ethanol, GABAA receptor, Ro 15-4513, alcohol antagonist, inverse agonist
Citation: Linden A-M, Schmitt U, Leppä E, Wulff P, Wisden W, Lüddens H and Korpi ER (2011) Ro 15-4513 antagonizes alcohol-induced sedation in mice through αβγ2-type GABAA receptors. Front. Neurosci. 5:3. doi: 10.3389/fnins.2011.00003
Received: 01 November 2010;
Accepted: 04 January 2011;
Published online: 20 January 2011.
Edited by:A. Leslie Morrow, University of North Carolina School of Medicine, USA
Reviewed by:Gregg E. Homanics, University of Pittsburgh, USA
Robert Adron Harris, University of Texas at Austin, USA
Copyright: © 2011 Linden, Schmitt, Leppä, Wulff, Wisden, Lüddens and Korpi. This is an open-access article subject to an exclusive license agreement between the authors and Frontiers Media SA, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are credited.
*Correspondence: Esa R. Korpi, Pharmacology, Institute of Biomedicine, University of Helsinki, POB 63 (Haartmaninkatu 8), FI-00014 Helsinki, Finland .e-mail: firstname.lastname@example.org; Hartmut Lüddens, Department of Psychiatry and Psychotherapy, University Medical Centre, Johannes Gutenberg University Mainz, Untere Zahlbacher Strasse 8, 55131 Mainz, Germany. e-mail: email@example.com