Low-dose alcohol actions on α4β3δ GABAA receptors are reversed by the behavioral alcohol antagonist Ro15-4513
Although it is now more than two decades since it was first reported that the imidazobenzodiazepine Ro15-4513 reverses behavioral alcohol effects, the molecular target(s) of Ro15-4513 and the mechanism of alcohol antagonism remain elusive. Here, we show that Ro15-4513 blocks the alcohol enhancement...
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 103; no. 22; pp. 8540 - 8545 |
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| Main Authors | , , |
| Format | Journal Article |
| Language | English |
| Published |
National Acad Sciences
30.05.2006
National Academy of Sciences |
| Series | From the Cover |
| Subjects | |
| Online Access | Get full text |
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| Summary: | Although it is now more than two decades since it was first reported that the imidazobenzodiazepine Ro15-4513 reverses behavioral alcohol effects, the molecular target(s) of Ro15-4513 and the mechanism of alcohol antagonism remain elusive. Here, we show that Ro15-4513 blocks the alcohol enhancement on recombinant “extrasynaptic” α4/6β3δ GABA A receptors at doses that do not reduce the GABA-induced Cl − current. At low ethanol concentrations (≤30 mM), the Ro15-4513 antagonism is complete. However, at higher ethanol concentrations (≥100 mM), there is a Ro15-4513-insensitive ethanol enhancement that is abolished in receptors containing a point mutation in the second transmembrane region of the β3 subunit (β3N265M). Therefore, α4/6β3δ GABA receptors have two distinct alcohol modulation sites: ( i ) a low-dose ethanol site present in α4/6β3δ receptors that is antagonized by the behavioral alcohol antagonist Ro15-4513 and ( ii ) a site activated at high (anesthetic) alcohol doses, defined by mutations in membrane-spanning regions. Receptors composed of α4β3N265Mδ subunits that lack the high-dose alcohol site show a saturable ethanol dose-response curve with a half-maximal enhancement at 16 mM, close to the legal blood alcohol driving limit in most U.S. states (17.4 mM). Like in behavioral experiments, the alcohol antagonist effect of Ro15-4513 on recombinant α4β3δ receptors is blocked by flumazenil and β-carboline-ethyl ester (β-CCE). Our findings suggest that ethanol/Ro15-4513-sensitive GABA A receptors are important mediators of behavioral alcohol effects. alcohol intoxication alcohol receptor anesthetics |
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| Bibliography: | Author contributions: M.W., H.J.H., and R.W.O. designed research; M.W. and H.J.H. performed research; M.W., H.J.H., and R.W.O. analyzed data; and M.W., H.J.H., and R.W.O. wrote the paper. Edited by Richard L. Huganir, Johns Hopkins University School of Medicine, Baltimore, MD, and approved April 7, 2006 M.W. and H.J.H. contributed equally to this work. |
| ISSN: | 0027-8424 1091-6490 |
| DOI: | 10.1073/pnas.0600194103 |