Low-dose alcohol actions on [alpha]4ß38 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...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2006-05, Vol.103 (22), p.8540
Main Authors: Wallner, M, Hanchar, H J, Olsen, R W
Format: Article
Language:English
Subjects:
Alcohol
Amino acids
Antagonist drugs
Behavior
Biochemistry
Ethanol
Molecular biology
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
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" α4/6ß3δ GABA^sub A^ receptors at doses that do not reduce the GABA-induced Cl^sup -^ 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 ß3 subunit (ß3N265M). Therefore, α4/6ß3δ GABA receptors have two distinct alcohol modulation sites: (i) a low-dose ethanol site present in α4/6ß3δ 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 α4ß3N265Mδ 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 α4ß3δ receptors is blocked by flumazenil and ß-carboline-ethyl ester (ß-CCE). Our findings suggest that ethanol/Ro15-4513-sensitive GABA^sub A^ receptors are important mediators of behavioral alcohol effects. [PUBLICATION ABSTRACT]
ISSN:0027-8424
1091-6490