Neuronal plasticity alterations including cytoskeletal dynamics and synaptic markers have been recently associated with the treatment of major depression. Here we investigated the effects of agomelatine, a novel antidepressant with melatonergic (MT1/MT2) agonist and 5-HT2C receptor antagonist properties, on cytoskeletal microtubular proteins and synaptic markers in the rat hippocampus, prefrontal cortex (PFC) and amygdala.

Adult male Sprague Dawley rats received daily i.p. administration of hydroxyethylcellulose 1% (vehicle) or agomelatine (40mg/kg) for 22 days. The rats were then sacrificed and hippocampi, PFC and amygdala dissected for analyses of microtubule dynamics markers (Tyr/Glu-Tub, Delta2-Tub and Acet-Tub) and synaptic markers (synaptophysin, PSD-95 and spinophilin) by Western blot.

In the PFC, agomelatine decreased Tyr/Glu-Tub and the neuronal-specific Delta2-Tub, suggesting decreased microtubule dynamics. In contrast, in the hippocampus Tyr/Glu-Tub and Delta2-Tub were increased, indicative of enhanced microtubule dynamics. A similar pattern to those seen in the hippocampus, but of higher magnitude, was observed in the amygdala where an important increase of Tyr/Glu-Tub accompanied by a decrease of the stable form Acet-Tub was observed. These findings were paralleled by decreased hippocampal spinophilin (dendritic spines marker), increased synaptophysin (pre-synaptic marker) and spinophilin in the PFC and amygdala and increased PSD-95 (post-synaptic marker) in the amygdala, all consistent with synaptic remodelling phenomena.

Taken together, these data shown that chronic agomelatine induces a differential modulation of microtubule dynamics and synaptic markers in the rat hippocampus, PFC and amygdala. These findings may have a particular relevance considering the fundamental role of these three brain areas in depression.