CHRONIC BENZODIAZEPINE EXPOSURE REGULATES GABA-A RECEPTOR EXRESSION IN RAT CEREBRAL CORTEX

MARÍA CLARA GRAVIELLE; MARÍA FLORENCIA FOITZICK; NELSY B. MEDINA

Córdoba

Congreso; XXXIII Reunión Anual de la Sociedad Argentina de Investigación en Neurociencias; 2018

Sociedad Argentina de Investigación en Neurociencias

Prolonged benzodiazepine exposure produces adaptive changes in GABA-A receptor structure and function that are associated with the development of tolerance. We have previously demonstrated that chronic benzodiazepine administration in rats results in tolerance to the sedative and anxiolytic effects which is accompanied with changes in the expression of GABA-A receptor alpha1 subunit in the cerebral cortex. The aim of this work was to investigate the molecular mechanism of benzodiazepine tolerance in an in vitro model of primary neuronal cultures from rat cerebral cortex. The exposure of cultured neurons to diazepam for 48 h produced a decrease in the interactions between GABA and benzodizepine binding sites (40 % uncoupling) which was prevented in the presence of nifedipine, a L-type voltage-gated calcium channel. Nifedipine also blocked the benzodiazepine-induced decrease in GABA-A receptor alpha1 subunit mRNA levels. Results from calcium mobilization and nuclear run-on assays suggested that the mechanism of tolerance is mediated by repression of alpha1 subunit gene expression induced by calcium influx through L-type voltage-gated calcium channels that would finally result in the uncoupling of GABA-A receptor allosteric interactions.