Prenatal stress (PS) in the rat is a well documented model of early stress that has high face and predictive validity as animal model of depression (Maccari et al. 2003; Morley-Fletcher et al. 2004). Indeed, PS rats present a life span reduction of hippocampal neurogenesis (Lemaire et al. 2000), increased anxiety and impairment of the feedback inhibition of the hypothalamus-pituitary adrenal axis. We here evaluated the effect of a chronic treatment (6 weeks, 40 mg/kg i.p. daily) with the new antidepressant agomelatine, a melatonin agonist with 5-HT2C antagonist properties, on hippocampal neurogenesis in PS male adult rats and, on PSA-NCAM expression, a marker of neuroplasticity. To investigate also the functional, behavioural impact of neurogenesis, we tested animals in the elevated-plus maze test to assess their anxiety-like response. To evidence neurogenesis and cell survival, the thymidine-analogue bromodeoxyuridine (BrdU, 75 mg/kg i.p. twice daily for 4 days) was injected after 3 weeks of the agomelatine treatment which was then continued for an additional 3 weeks. The results indicate a markedly reduced neurogenesis in the dentate gyrus of PS rats and an enhanced PSA-NCAM expression (ANOVA, group by treatment interaction, F(1,21) = 10.53, P < 0.01). The effects of PS were reversed by the chronic agomelatine treatment Agomelatine’s effect on survival was selectively observed in the ventral part of the dentate gyrus (ANOVA region by group by treatment interaction, F(1,26) = 4.73, P < 0.05), a brain region specifically involved in anxiety (Kjesltrup et al. 2002). Moreover in PS animals agomelatine did not modify the ratio between neurons and glial cells assessed by NeuN and GFAP labelling. Behaviourally, PS rats treated with agomelatine spent more time on the open arms of the elevated plus maze, (ANOVA, group by treatment interaction, F(1,27 ) = 7.06, P < 0.05) suggesting a possible causal link between increased hippocampal neurogenesis and attenuated anxiety-like behaviour in a validated model of depression. The results obtained with agomelatine provide further evidence of neuroplasticity as one of the targets of antidepressants and further reinforce the high predictive validity of the PS rat as animal model of depression.