Tianeptine induces expression of dual specificity phosphatases and evokes rebound emergence of cortical slow wave electrophysiological activity

Abstract

Background: The precise mechanism governing the antidepressant effects of tianeptine is unknown. Modulation of brain glutamatergic neurotransmission has been however implicated, suggesting potential shared features with rapid-acting antidepressants targeting N-methyl-D-aspartate receptors (NMDAR). Our recent studies suggest that a single subanesthetic dose of NMDAR antagonists ketamine or nitrous oxide (N₂O) gradually evoke 1-4 Hz electrophysiological activity (delta-rhythm) of cerebral cortex that is accompanied by molecular signaling associated with synaptic plasticity (e.g. activation of tropomyosin receptor kinase B (TrkB) and inhibition of glycogen synthase kinase 3β (GSK3β)).

Methods: We have here investigated the time-dependent effects of tianeptine (30 mg/kg, i.p.) on electrocorticogram, focusing on potential biphasic regulation of the delta-rhythm. Selected molecular markers associated with ketamine's antidepressant effects were analyzed in the medial prefrontal cortex after the treatment using quantitative polymerase chain reaction and western blotting.

Results: An acute tianeptine treatment induced changes of electrocorticogram typical for active wakefulness that lasted for 2-2.5 h, which was followed by high amplitude delta-activity rebound. The levels of Arc and Homer1a, but not c-Fos, BdnfIV and Zif268, were increased by tianeptine. Phosphorylation of mitogen-activated protein kinase (MAPK), TrkB and GSK3β remained unaltered at 2-hours and at 3-hours post-treatment. Notably, tianeptine also increased the level of mRNA of several dual specificity phosphatases (Duspss) - negative regulators of MAPK.

Conclusion: Tianeptine produces acute changes of electrocorticogram resembling rapid-acting antidepressants ketamine and N₂O. Concomitant regulation of Dusps may hamper the effects of tianeptine on MAPK pathway and influence the magnitude of homeostatic emergence of delta-activity and TrkB-GSK3β signaling.

Keywords: Delta-activity; Dusp; Electrocorticogram; Homer1; MAPK; Tianeptine.