REGULATION OF GABAA RECEPTOR EXPRESSION INDUCED BY PROLONGED BENZODIAZEPINE STIMULATION DEPENDS ON THE ACTIVATION OF L-TYPE VOLTAGE-GATED CALCIUM CHANNELS

MICAELA PIETKO; MICAELA PIETKO; NELSY BEATRIZ MEDINA; NELSY BEATRIZ MEDINA; MARIA CLARA GRAVIELLE; MARIA CLARA GRAVIELLE

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Congreso; Reunión Anual de Sociedades de Biociencias; 2020

Sociedad Argentina de Investigaciones Clínicas

Persistent stimulation of GABAA receptors by positive allosteric modulators, such as benzodiazepines, barbiturates, neurosteroids and ethanol, induces adaptive changes that result in tolerance. In particular, the clinical use of benzodiazepines has been limited by the development of tolerance to most of their pharmacological actions. Although different alterations in the structure and function of the GABAA receptors have been described, the signaling pathways activated by sustained exposure to benzodiazepines remain unknown. The aim of this work was to elucidate the signaling cascade triggered by prolonged benzodiazepine treatments that lead to downregulation of GABAA receptor alpha 1 subunit. To this end, primary neuronal cultures from rat cerebral cortex were treated with diazepam (25 μM), a classical benzodiazepine, for 48 h. At the end of this incubation, cells were collected for biochemical and molecular biological experiments. Flunitrazepam binding experiments showed that diazepam induced uncoupling between GABA and benzodiazepine sites (40 %, p