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The Journal of Neuroscience, July 28, 2004, 24(30):6785-6790; doi:10.1523/JNEUROSCI.1067-04.2004

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Behavioral/Systems/Cognitive
Requirement of {alpha}5-GABAA Receptors for the Development of Tolerance to the Sedative Action of Diazepam in Mice

Carolien van Rijnsoever,1 * Marcus Täuber,1 * Mohamed Khaled Choulli,1 Ruth Keist,1 Uwe Rudolph,1 Hanns Mohler,1,2 Jean Marc Fritschy,1 and Florence Crestani1

1Institute of Pharmacology and Toxicology, University of Zürich, 8057 Zürich, Switzerland, and 2Department of Applied Biosciences, Swiss Federal Institute of Technology, 8057 Zürich, Switzerland

Despite its pharmacological relevance, the mechanism of the development of tolerance to the action of benzodiazepines is essentially unknown. The acute sedative action of diazepam is mediated via {alpha}1-GABAA receptors. Therefore, we tested whether chronic activation of these receptors by diazepam is sufficient to induce tolerance to its sedative action. Knock-in mice, in which the{alpha}1-,{alpha}2-,{alpha}3-, or{alpha}5-GABAA receptors had been rendered insensitive to diazepam by histidine-arginine point mutation, were chronically treated with diazepam (8 d; 15 mg · kg-1 · d-1) and tested for motor activity. Wild-type, {alpha}2(H101R), and {alpha}3(H126R) mice showed a robust diminution of the motor-depressant drug action. In contrast, {alpha}5(H105R) mice failed to display any sedative tolerance. {alpha}1(H101R) mice showed no alteration of motor activity with chronic diazepam treatment. Autoradiography with [3H]flumazenil revealed no change in benzodiazepine binding sites. However, a decrease in {alpha}5-subunit radioligand binding was detected selectively in the dentate gyrus with specific ligands. This alteration was observed only in diazepam-tolerant animals, indicating that the manifestation of tolerance to the sedative action of diazepam is associated with a downregulation of {alpha}5-GABAA receptors in the dentate gyrus. Thus, the chronic activation of {alpha}5-GABAA receptors is crucial for the normal development of sedative tolerance to diazepam, which manifests itself in conjunction with {alpha}1-GABAA receptors.

Key words: diazepam; GABAA receptor; tolerance; motor activity; dentate gyrus; knock-in mice

Received March 23, 2004; revised June 1, 2004; accepted June 16, 2004.




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[Abstract] [Full Text] [PDF]


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