Diazepam-induced transcriptional regulation of GABAA receptor alpha 1 subunit via L-type voltage-gated calcium channel activation1 subunit gene in rat cerebrocortical neurons

MARÍA FLORENCIA FOITZICK; NELSY BEATRIZ MEDINA; MARIA CLARA GRAVIELLE; LUCÍA CANDELA IGLESIAS GARCÍA

Mar del Plara

Congreso; Reunión Anual de Sociedades de Biociencia; 2019

Sociedad Argentina de Investigaciones Clínicas

GABA-A receptors are targets of different pharmacologically relevant drugs, such as barbiturates, benzodiazepines, and anesthetics. In particular, benzodiazepines are prescribed for the treatment of anxiety, sleep disorders, and seizure disorders. Prolonged activation of GABA-A receptors by endogenous and exogenous modulators induces adaptive changes that lead to tolerance. For example, chronic administration of benzodiazepines produces tolerance to most of their pharmacological actions, limiting their usefulness. The mechanism of tolerance is still unknown. We have previously demonstrated that chronic diazepam administration in rats results in tolerance to the sedative and anxiolytic effects which is accompanied with a decrease in the interactions between GABA and benzodizepine binding sites (uncoupling) incerebral 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 40 % uncoupling (p<0.05) which was prevented in the presence of nifedipine, an inhibitor of L-type voltage-gated calcium channels (L-VGCCs). Benzodiazepine treattment also induced a 45 % decrease (p