Quinone reductase 2 and antidepressant effect of melatonin derivatives

Melatonin and its immediate precursor, N-acetylserotonin (NAS), exert antidepressant effects in experimental models and clinical studies. We reported that melatonin and NAS decreased immobility time (an indicator of antidepressant activity) in the mouse tail suspension test. Melatonin type 3 receptor (MT3) was identified as the same protein as quinone reductase 2 (QR2) detoxifying and antioxidant enzyme. To further elucidate the role of QR2/MT3 in antidepressant action of NAS and melatonin, we studied the effect of QR2/MT3 agonist and antagonist in a tail suspension test. QR2/MT3 agonist 5-MCA-NAT decreased, while the QR2/MT3 antagonist prazosin increased the duration of immobility in the tail suspension test in a dose-dependent manner. Prazosin, in a dose that did not affect the duration of immobility, attenuated the antidepressant-like effect of NAS, melatonin, and typical tricyclic antidepressant, amitriptyline, in the tail suspension test. Our results suggest that the modulation of QR2/MT3 might contribute to mechanism(s) of antidepressant effect. New antidepressants might be searched among the agonists of QR2/MT3.