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

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• 作者：Jardel Gomes Villarinho ; Roselei Fachinetto ; Francielle de Vargas Pinheiro ; Gabriela da Silva Sant'Anna ; Pablo Machado ; Patr¨ªcia Andr¨¦ia Dombrowski ; Cl¨¢udio da Cunha ; Daniela de Almeida Cabrini ; Marcos Ant?nio Pinto Martins ; Helio Gauze Bonacorso ; Nilo Zanatta ; Maribel Antonello Rubin ; Juliano Ferreira
• 关键词：Depression ; Monoamine metabolism ; Moclobemide ; Reversible MAO-A inhibitor
• 刊名：Progress in Neuro-Psychopharmacology and Biological Psychiatry
• 出版年：2012
• 出版时间：1 October, 2012
• 年：2012
• 卷：39
• 期：1
• 页码：31-39
• 全文大小：1039 K

文摘

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) ¦ÌM and 46.67 (31.8-68.4) ¦ÌM 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 ¦Ìmol/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 ¦Ìmol/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 ¦Ìmol/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.