PERSONAL DE APOYO
FERRERI maria celeste
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, MC; GUTIERREZ, ML; GRAVIELLE, MC
Revista:
INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE
Editorial:
PERGAMON-ELSEVIER SCIENCE LTD
Referencias:
Lugar: Amsterdam; Año: 2015
ISSN:
0736-5748
Resumen:
The clinical use of benzodiazepines is limited bythe development of tolerance to their pharmacologicaleffects. Tolerance to each of the pharmacological actionsof benzodiazepines develops at different rates. The aim ofthis work was to investigate the mechanism of toleranceby performing behavioral tests in combination with biochemicalstudies. To this end, we administered prolongedtreatments of diazepam to rats for 7 or 14 days. Toleranceto the sedative effects of diazepam was detected by meansof the open field test after the 7- and 14-day treatments,whereas tolerance to the anxiolytic actions of benzodiazepinemanifested following only the 14-day treatment inthe elevated plus maze. The cerebral cortical concentrationsof diazepam did not decline after the diazepam treatments,indicating that tolerance was not due to alterations in pharmacokineticfactors. The uncoupling of GABA/benzodiazepinesite interactions and an increase in the degree ofphosphorylation of the GABAA receptor c2 subunit at serine327 in the cerebral cortex were produced by day 7 of diazepamtreatment and persisted after 14 days of exposure tobenzodiazepine. Thus, these alterations could be part ofthe mechanism of tolerance to the sedative effects of diazepam.An increase in the percentage of a1-containing GABAAreceptors in the cerebral cortex was observed following the14-day treatment with diazepam but not the 7-day treatment,suggesting that tolerance to the anxiolytic effects isassociated with a change in receptor subunit composition.The understanding of the molecular bases of tolerancecould be important for the development of new drugs thatmaintain their efficacies over long-term treatments. 2015 IBRO. Published by Elsevier Ltd. All rights reserved.
