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★ Effects of imipramine in maternal deprived (MD) rats. ★ Imipramine presented antidepressant-like effects. ★ Imipramine regulated the pro-inflammatory cytokines in MD rats. ★ Imipramine regulated BDNF levels in MD rats.A growing body of evidence is pointing toward an association between immune molecules, as well brain-derived neurotrophic factor (BDNF) and the depression. The present study was aimed to evaluate the behavioral and molecular effects of the antidepressant imipramine in maternally deprived adult rats. To this aim, maternally deprived and non-deprived (control group) male rats were treated with imipramine (30 mg/kg) once a day for 14 days during their adult phase. Their behavior was then assessed using the forced swimming test. In addition to this, IL-10, TNF-α and IL-1β cytokines were assessed in the serum and cerebrospinal fluid (CSF). In addition, BDNF protein levels were assessed in the prefrontal cortex, hippocampus and amygdala. In deprived rats treated with saline was observed an increase on immobility time, compared with non-deprived rats treated with imipramine (p < 0.05). Deprived rats treated with saline presented a decrease on BDNF levels in the amygdala (p < 0.05), compared with all other groups. The IL-10 levels were decreased in the serum (p < 0.05). TNF-α and IL-1β levels were increased in the serum and CSF of deprived rats treated with saline (p < 0.05). Interestingly, imipramine treatment reversed the effects of maternal deprivation on BDNF and cytokines levels (p < 0.05). Finally, these findings further support a relationship between immune activation, neurotrophins and the depression, and considering the action of imipramine, it is suggested that classic antidepressants could exert their effects by modulating the immune system.