| Autor: |
van Rijnsoever C; Institute of Pharmacology and Toxicology, University of Zürich, 8057 Zürich, Switzerland., Täuber M, Choulli MK, Keist R, Rudolph U, Mohler H, Fritschy JM, Crestani F |
| Jazyk: |
angličtina |
| Zdroj: |
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2004 Jul 28; Vol. 24 (30), pp. 6785-90. |
| DOI: |
10.1523/JNEUROSCI.1067-04.2004 |
| 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 alpha1-GABA(A) 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 thealpha1-,alpha2-,alpha3-, oralpha(5)-GABA(A) receptors had been rendered insensitive to diazepam by histidine-arginine point mutation, were chronically treated with diazepam (8 d; 15 mg x kg(-1) x d(-1)) and tested for motor activity. Wild-type, alpha2(H101R), and alpha3(H126R) mice showed a robust diminution of the motor-depressant drug action. In contrast, alpha5(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 alpha5-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 alpha5-GABA(A) receptors in the dentate gyrus. Thus, the chronic activation of alpha(5)-GABA(A) receptors is crucial for the normal development of sedative tolerance to diazepam, which manifests itself in conjunction with alpha1-GABA(A) receptors. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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