| Autor: |
Van Rijnsoever, Carolien, Täuber, Marcus, Choulli, Mohamed Khaled, Keist, Ruth, Rudolph, Uwe, Mohler, Hanns, Fritschy, Jean Marc, Crestani, Florence |
| Předmět: |
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| Zdroj: |
Journal of Neuroscience; 7/28/2004, Vol. 24 Issue 30, p6785-6790, 6p, 1 Chart, 2 Graphs |
| Abstrakt: |
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 the α1--,α2-, α3-, or α5-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, αa(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, &alpha1(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 as-GABAA receptors is crucial for the normal development of sedative tolerance to diazepam, which manifests itself in conjunction with α1-GABAA receptors. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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