IBBEA   24401
INSTITUTO DE BIODIVERSIDAD Y BIOLOGIA EXPERIMENTAL Y APLICADA
Unidad Ejecutora - UE
artículos
Título:
Tolerance to the sedative and anxiolytic effects of diazepam is associated with different alterations of GABAA receptors in rat cerebral cortex
Autor/es:
FERRERI, M. C.; GUTIÉRREZ, M. L.; GRAVIELLE, M. C.
Revista:
NEUROSCIENCE
Editorial:
PERGAMON-ELSEVIER SCIENCE LTD
Referencias:
Lugar: Amsterdam; Año: 2015 vol. 310 p. 152 - 162
ISSN:
0306-4522
Resumen:
The clinical use of benzodiazepines is limited by the development of tolerance to theirpharmacological effects. Tolerances to each of the pharmacological actions ofbenzodiazepines develop at different rates. The aim of this work was to investigate themechanism of tolerance by performing behavioral tests in combination withbiochemical studies. To this end, we administered prolonged treatments of diazepam torats for 7 or 14 days. Tolerance to the sedative effects of diazepam was detected bymeans of the open field test after the 7- and 14-day treatments, whereas tolerance to theanxiolytic actions of the benzodiazepine manifested following only the 14-day treatmentin the elevated plus maze. The cerebral cortical concentrations of diazepam did notdecline after the diazepam treatments, indicating that tolerance was not due toalterations in pharmacokinetic factors. The uncoupling of GABA/benzodiazepine siteinteractions and an increase in the degree of phosphorylation of the GABAA receptor 2subunit at serine 327 in the cerebral cortex were produced by day 7 of diazepamtreatment and persisted after 14 days of exposure to the benzodiazepine. Thus, thesealterations could be part of the mechanism of tolerance to the sedative effects ofdiazepam. An increase in the percentage of α1-containing GABAA receptors in thecerebral cortex was observed following the 14-daytreatment with diazepam but not the7-day treatment, suggesting that tolerance to the anxiolytic effects is associated with achange in receptor subunit composition. The understanding of the molecular bases oftolerance could be important for the development of new drugs that maintain theirefficacies over long-term treatments