To the best of our

To the best of our knowledge, this is the first report on the effect of chronic SSRI treatment on the acquisition and selinexor of fear-potentiated startle in rodents. The lack of effect on expression of cued fear is in line with the single human fear-potentiated startle study available (Grillon et al., 2009). The finding that neither acute nor chronic paroxetine treatment affected the acquisition and expression of cued conditioned fear suggests that the fear learning deficit found in SERT−/− is due to developmental changes and does not result from compromised SERT functioning during fear learning. Serotonin is known to modulate neurodevelopment (Gaspar et al., 2003, Lauder, 1990) and the neural systems regulating anxiety-like behavior are especially sensitive to changes in serotonergic functioning during early development (Gross et al., 2002, Vinkers et al., 2010). It has already been reported that SERT−/− mice show increased spine density and excitatory drive of the BLA (Wellman et al., 2007). Such changes in neuronal structure and excitability may also be responsible for the learning deficit observed in SERT−/− rats. However, the exact mechanism underlying this deficit in SERT−/− rats is subject of further investigation. Interestingly, acute administration of paroxetine during fear acquisition did increase overall startle responding 24h later, which suggests that acute SERT inhibition potentiates the acquisition of contextual conditioned fear. To the best of our knowledge, this is the first time the acute anxiogenic effect of SSRIs in humans, as measured with fear-potentiated startle, is shown in rodents (Burghardt et al., 2004, Grillon et al., 2007a). Together with findings from our concurrent study in humans that SERT S/S carriers show exaggerated contextual fear learning (Heitland et al., 2013), these results suggest that increased extracellular serotonin levels may also be responsible for the increased contextual conditioned fear seen in SERT−/− rats. Findings from the present study indicate that CRF1 receptors are especially important in fear acquisition. CP154,526 given before acquisition training, at least partly, reinstated the fear-potentiated startle response and blocked the development of contextual conditioned fear in SERT−/− rats. CP154,526 administered to pre-trained rats however, neither normalized the expression of fear-potentiated startle nor blocked contextual conditioned fear in SERT−/− rats. This absence of effect of CP154,526 on fear expression in pre-trained rats is consistent with accumulating evidence that CRF1 receptor antagonists do not affect the expression of fear-potentiated startle (de Jongh et al., 2003, Walker et al., 2009). In addition, together with the findings from our concurrent study in humans that interactions between SERT and the CRF1 receptor play a pivotal role in the regulation of conditioned fear acquisition in healthy subjects (Heitland et al., 2013), this study not only supports the idea that especially the interplay between the CRF and serotonin systems regulates fear learning, but also emphasizes the translational value of the fear-potentiated startle paradigm.