Antidepressant-like effect of the novel MAO inhibitor 2-(3,4-dimethoxy-phenyl)-4,5-dihydro-1H-imidazole (2-DMPI) in mice

Abstract

Monoamine oxidase (MAO) inhibitors were the first antidepressant drugs to be prescribed and are still used today with great success, especially in patients resistant to other antidepressants. In this study, we evaluated the MAO inhibitory properties and the potential antidepressant action of 2-(3,4-dimethoxy-phenyl)-4,5-dihydro-1H-imidazole (2-DMPI) in mice. We found that 2-DMPI inhibited both MAO isoforms (K(i) values were 1.53 (1.3-1.8) μM and 46.67 (31.8-68.4) μM for MAO-A and MAO-B, respectively) with 30-fold higher selectivity toward MAO-A. In relation to the nature of MAO-A inhibition, 2-DMPI showed to be a mixed and reversible inhibitor. The treatment with 2-DMPI (100-1000 μmol/kg, s.c.) caused a significant decrease in immobility time in the tail suspension test (TST) without affecting locomotor activity, motor coordination or anxiety-related activities. Conversely, moclobemide (1000 μmol/kg, s.c.) caused a significant increase in immobility time in the TST, which appeared to be mediated by a nonspecific effect on motor coordination function. 2-DMPI (300 μmol/kg, s.c.) decreased serotonin turnover in the cerebral cortex, hippocampus and striatum, whereas dopamine turnover was diminished only in the striatum, and norepinephrine turnover was not changed. The antidepressant-like effect of 2-DMPI was inhibited by the pretreatment of mice with methysergide (2 mg/kg, s.c., a non-selective serotonin receptor antagonist), WAY100635 (0.1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist) or haloperidol (0.05 mg/kg, i.p., a non-selective dopamine receptor antagonist). These results suggest that 2-DMPI is a prototype reversible and preferential MAO-A inhibitor with potential antidepressant activity, due to its modulatory effect on serotonergic and dopaminergic systems.