A gene variant in the human serotonin transporter (SERT) can increase the vulnerability to mood disorders. SERT knockout animals show similarities to the human condition and represent an important tool to investigate the mechanisms underlying the pathologic condition in humans. Along this line of thinking, we used SERT KO rats (SERT(+/-) and SERT(-/-)) to investigate abnormalities in the expression and function of the activity-regulated gene Arc (Activity-regulated cytoskeletal associated protein) and the early inducible gene Zif-268, (zinc finger binding protein clone 268), which are important players in neuronal plasticity. We found lower basal Arc mRNA levels in hippocampus and prefrontal cortex of mutant rats in comparison with wild-type animals. Moreover SERT mutant rats show altered stress responsiveness. Indeed an acute swim stress significantly up-regulated the levels of Arc mRNA in hippocampus and prefrontal cortex, as well as of Zif-268 in frontal cortex, only in SERT(+/-) and SERT(-/-) rats. These alterations may be associated to behavioral traits linked to SERT and may contribute to the neuroplastic and morphological changes observed in depression.