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

M. C. FERRERI; M. C. GRAVIELLE

Mar del Plata

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

The clinical use of benzodiazepines is limited by the development oftolerance. The aim of this work was to investigate the mechanism of toleranceby performing behavioral tests in combination with biochemical studies. To thisend, we administered chronic treatments of diazepam to rats for 7 or 14 days.Tolerance to the sedative effects of diazepam was detected after the 7- and14-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 serine 327 in the cerebral cortex were produced by day 7 ofdiazepam treatment and persisted after 14 days of exposure to the benzodiazepine.Thus, these alterations could be part of the mechanism of tolerance to the sedativeeffects of diazepam. An increase in the percentage of α1-containing GABAA receptors in the cerebral cortex was observedfollowing the 14-day treatment with diazepam but not the 7-day treatment,suggesting that tolerance to the anxiolytic effects is associated with a changein receptor subunit composition. Our results suggest that tolerance to the sedativeand anxiolytic effects of diazepam is mediated by different mechanisms.