RT Journal Article
SR Electronic
T1 Requirement of α5-GABAA Receptors for the Development of Tolerance to the Sedative Action of Diazepam in Mice
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 6785
OP 6790
DO 10.1523/JNEUROSCI.1067-04.2004
VO 24
IS 30
A1 Carolien van Rijnsoever
A1 Marcus Täuber
A1 Mohamed Khaled Choulli
A1 Ruth Keist
A1 Uwe Rudolph
A1 Hanns Mohler
A1 Jean Marc Fritschy
A1 Florence Crestani
YR 2004
UL http://www.jneurosci.org/content/24/30/6785.abstract
AB 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 α1-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 theα1-,α2-,α3-, orα5-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, α2(H101R), and α3(H126R) mice showed a robust diminution of the motor-depressant drug action. In contrast, α5(H105R) mice failed to display any sedative tolerance. α1(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 α5-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 α5-GABAA receptors in the dentate gyrus. Thus, the chronic activation of α5-GABAA receptors is crucial for the normal development of sedative tolerance to diazepam, which manifests itself in conjunction with α1-GABAA receptors.