Agomelatine is a novel and clinically effective antidepressant drug with melatonergic (MT1 /MT2) agonist and 5-HT_(2C) receptor antagonist properties. Both receptorial components are widely expressed in the central nervous system and it seems that this compound could act synergistically on both the melatonergic and the 5-HT_(2C) receptors. In this review we will briefly summarize the preclinical evidence suggesting that the molecular-cellular effects of agomelatine and in turn its antidepressant activity are the result of a synergistic action between its agonism at MT1 /MT2 and antagonism at 5-HT_(2C) receptors. The antidepressant properties of agomelatine related to its effect on neurogenesis, cell survival, brain-derived neurotrophic factor (BDNF), activity-regulated cytoskeleton associated protein (Arc) and stress-induced glutamate release, appear to be due to this synergistic action. Compared with traditional antidepressants which also affect these parameters, agomelatine is the only one able to resynchronize these effectors at distinct levels, circuital and intracellular. This suggests that agomelatine effects in restoring circadian rhythms and relieving depressive symptoms result from a synergistic interaction between melatonergic and serotonergic receptors.
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