5-HT1A receptor agonist properties of DNA methyltransferase inhibitor decitabine in mice exposed to the forced swim test.

Abstract

Decitabine is a nucleoside analog that inhibits DNA methyltransferases with therapeutic potential in stress-related disorders, including depression. Serotonin (5-HT) plays a crucial role in stress response and depression through its receptors, especially 5-HT1A receptors (5-HT1AR). Decitabine treatment has shown rapid-acting antidepressant-like effects in different preclinical models, similar to those observed with ketamine. In addition to modulating neuroplastic mechanisms, the antidepressant effects of ketamine have also been associated with serotonergic (5-HT) signaling, including the activation of 5-HT1AR. However, the mechanisms underlying antidepressant action induced by decitabine are still poorly understood. Therefore, this work aimed to investigate the participation of 5-HT in the stress-coping behavior induced by decitabine in the forced swim test (FST), a predictive test of antidepressant effects, by: 1) evaluating if 5-HT1AR antagonism and/or 5-HT depletion would impair decitabine-induced behavioral effects; and 2) analyzing the potential binding of decitabine to 5-HT1AR by molecular docking analysis. Results showed that decitabine (0.2 mg/kg) induced antidepressant-like effects in mice subjected to FST. Pretreatment with WAY100635 (a 5-HT1AR antagonist: 0.1 mg/kg, i.p.), but not PCPA (an inhibitor of 5-HT synthesis: 150 mg/kg, i.p., once per day for 4 days), blocked the effects of decitabine in the FST, indicating the participation of 5-HT1AR independent of 5-HT levels. In silico analysis showed that decitabine exhibits an interaction profile with 5-HT1AR very similar to that of 5-HT, suggesting a direct action of decitabine on these receptors. None of the treatments induced locomotor effects. Our results suggest that the behavioral effect of decitabine in the FST depends on direct activation of 5-HT1AR.