USE-DEPENDENT REGULATION OF GABA-A RECEPTORS IN RAT CEREBRAL CORTEX

MARIA CLARA GRAVIELLE; CAMILA PARRA

Buenos Aires

Congreso; Segundo Congreso de FALAN (Federation of Latin American and Caribbean Neuroscience Societies); 2016

Federation of Latin American and Caribbean Neuroscience Societies

Regulation of GABA-A receptor function by persistentactivation can occur under physiological and pharmacological conditions. Inparticular, chronic benzodiazepineadministration induces adaptive changes in GABA-A receptors thatconstitute an example of neuronal plasticity. We have previously demonstratedthat prolonged benzodiazepine administration in rats results in tolerance tothe sedative and anxiolytic effects that is associated with changes in GABA-Areceptors in the cerebral cortex. The aim of this work was to continueinvestigating the molecular mechanism of benzodiazepine tolerance in an in vitro model of primary neuronalcultures from rat cerebral cortex. The exposure of cultured neurons to diazepamfor 48 h produced an uncoupling of GABA/benzodiazepine site interactions. Thisuncoupling was prevented in the presence of flumazenil or picrotoxin,suggesting that depends on the binding of benzodiazepine to its specificrecognition site and the GABA-A receptor activation. Uncoupling was alsoblocked by nifedipine, a L-type voltage-gated calcium channel. In addition,diazepam treatment induced a decrease in GABA-A receptor alpha1 subunit mRNAlevels that is prevented by nifedipine. These results suggest that themechanism of tolerance is mediated by repression of alpha1 subunit geneexpression induced by calcium influx through L-type voltage-gated calciumchannels that would finally result in the uncoupling of GABA-A receptorallosteric interactions.