TOLERANCE TO DIAZEPAM IS ASSOCIATED WITH DIFFERENT ALTERATIONS OF GABAA RECEPTORS IN RAT CEREBRAL CORTEX

FERRERI, M. C.; GRAVIELLE, M. C.

Mar del Plata

Congreso; XXX Congreso Anual de la Sociedad Argentina de Investigación en Neurociencias; 2015

Sociedad Argentina de Investigación en Neurociencias

The clinical use of benzodiazepines is limitedby the development of tolerance. The aim of this work was to investigate the mechanismof tolerance by performing behavioral tests in combination with biochemical studies.To this end, we administered chronic treatments of diazepam to rats for 7 or 14days. Tolerance to the sedative effects of diazepam was detected after the 7-and 14-day treatments, whereas tolerance to the anxiolytic actions of the benzodiazepinemanifested following only the 14-day treatment. The cerebral corticalconcentrations of diazepam did not decline after the chronic treatments,indicating that tolerance was not due to alterations in pharmacokineticfactors. The uncoupling of GABA/benzodiazepine site interactions and anincrease in the degree of phosphorylation of the GABAA receptor g2 subunit at serine327 in the cerebral cortex were produced by day 7 of diazepam treatment andpersisted after 14 days of exposure to the benzodiazepine. Thus, thesealterations could be part of the mechanism of tolerance to the sedative effectsof diazepam. An increase in the percentage of α1-containing GABAA receptors in thecerebral cortex was observed following the 14-day treatment with diazepam butnot the 7-day treatment, suggesting that tolerance to the anxiolytic effects isassociated with a change in receptor subunit composition. Our results suggestthat tolerance to the sedative and anxiolytic effects of diazepam is mediatedby different mechanisms.