PROLONGED EXPOSURE OF CORTICAL NEURONS TO DIAZEPAM INDUCES DOWNREGULATION OF GABAA RECEPTOR α1 SUBUNIT VIA A CALCIUM/ PROTEIN KINASE A SIGNALING PATHWAY

L. CAROLINA GONZÁLEZ GÓMEZ; SARA SANZ BLASCO; MARIA CLARA GRAVIELLE

Mar del Plata

Congreso; Reunión Anual de las Sociedades de Biociencias; 2023

Sociedad Argentina de Investigaciones Clínicas

Benzodiazepines exhibit a high therapeutic index and low toxicity in short-term treatments, however, prolonged administration induces tolerance to most of their therapeutic actions. In previous studies, we demonstrated that the prolonged exposure of rat cortical neurons to diazepam (DZ) produces a transcriptional repression of the GABAA receptor α1 subunit gene. This regulatory mechanism depends on the activation of L-type voltage gated calcium channels (L-VGCC). The aim of this work was to investigate the signaling cascade triggered by the benzodiazepine-induced stimulation of calcium influx that leads to the regulation of the GABAA receptor expression. To this end, we exposed rat neuronal cultures to DZ (1 μM) for 48h in the presence or absence of different inhibitors. Results from this study indicated that the DZ-induced decrease in the mRNA and protein levels of the α1 subunit was inhibited in the presence of 1 μM H-89, a protein kinase A (PKA) inhibitor (p