292 a Psychopharmacology (2012) 223:281–297 b c d Fig. 4 Example images of Nr4a1 (a), Egr1 (b), c-fos (c) and Id1 (d) mRNA expression as assessed by ISH (up) and quantification results for mRNA expression of these genes in the CCX in groups treated for 3 days with CIT repeatedly and in a single dose (down). Data represent duration have not been clearly identified, although some of the alterations reported were also observed in our study, i.e., Arrb1, Cdk5, Sst, and Jund. Changes in the expression of Hspb1, c-fos, Crhbp, Egr1, Npy, glutamate ionotropic recep- tors, Pax6, and members of the ATPase Ca2+ transporter family observed in our study were also reported by Conti et al. (2007) following electroconvulsive shock (ECS), sleep deprivation, and fluoxetine. Some evidence for the importance of ion transport in the rat brain cortex have been reported in the context of antide- pressant treatment (Knuuttila et al. 2004; Palotas et al. 2004). Specifically, changes in calcium channels (Cacna and Cacnb) and voltage-gated sodium channels (Scn11a) were observed after 28 days of treatment with amitryptiline (Boehm et al. 2006). In the present study, a change in Gria1–3, Scn2a1, and Cacna1a gene expression also oc- curred. Gria1 and Gria3 encode the subunits GLUR1 and GLUR3 of the glutamate ionotropic receptor (AMPA), which are implicated in the mechanism of action of ADs (Ampuero et al. 2010; Du et al. 2004; Knuuttila et al. 2004; Martinez-Turrillas et al. 2002). The important feature of ADs treatment is the delayed onset of therapeutic effects (Machado-Vieira et al. 2010). However, some reports indicate that treatment with selective serotonin reuptake inhibitors (SSRIs) is associated with symptomatic improvement by the end of the first week or even as quickly as within the first 3 days of treatment (Taylor et al. 2006; Mitchell 2006; Katz et al. 2004). These clinical observations could reflect changes on the molecular level shortly after the initiation of therapy. The results of the present study clearly showed that expression changes of most affected genes occurred in the first 3 days of treatment after both drugs. Such immediate changes in gene expression were apparent not only when individual genes were analyzed but also in a global view of gene expression in the SVD diagrams. The observed gene expression patterns were highly dynamic, with oscillations and peaks occurring at different time points. Such temporal fluctuations during ADs treatment may be a reason for the discrepancies of results available from the the mean optical density±SEM (PSL/mm2) normalized to the control. Student’s t test was used as post hoc test to compare the 3-day-treated groups vs the control group; *p<0.05 literature which were often obtained at different time points of treatment. DMI, which influences noradrenaline reuptake, is known to change the expression of mRNA encoding the noradrenaline transporter in the rat locus ceruleus in a biphas- ic manner with a decrease after 7 days and an increase after 14 days of treatment (Zhu et al. 2002). Such biphasic changes are also seen for SSRI treatment of rats, with a temporary reduction of serotonin transporter mRNA after 7 days but not 21 days of treatment with fluoxetine (Neumaier et al. 1996). Additionally, changes in other cellular components (not di- rectly linked to the monoamine reuptake inhibition) are also described by time-dependent fluctuations of either mRNA or protein levels. For example, the level of the glutamate iono- tropic receptor GRIA2/3 reaches a peak after 7 and 21 days, but not 14 days, of treatment with DMI (Martinez-Turrillas et al. 2002), and the levels of the transcription factor AP-2 and its DNA-binding activity are decreased after 7 days, but not 21 days, of treatment with CIT (Berggard et al. 2003). There is also upregulation of glucocorticoid receptor in the hippo- campus by 2 and 14 days, but not 7 days, exposure to tricyclic antidepressants (Okugawa et al. 1999). Expression of BDNF after ADs is another example: the significant decrease in expression occurs after 4 days of fluoxetine, while chronic administration of ADs induces increased BDNF expression (de Foubert et al. 2004). From these data, it is clear that dependence of various measures on the duration of ADs treatment has already been noticed, however, not dwelled upon any further, especially in the context of any compensatory adaptations. Analyses performed in the present work indicated an inter- esting pattern of expression of immediate early genes (IEGs: c-fos, Egr1, and Nr4a1). Egr1 (also known as zif268, Krox-24, and NGFI-A) has been extensively used as a marker of neu- ronal responses to sensory stimuli. Despite the fact that changes in the expression of c-fos and Egr1 are both consid- ered to reflect neuronal activity, their expression patterns after acute ADs treatment differ between brain regions (Slattery et al. 2005), similar to our study. Chronic (6 or 9 days) ECS or treatment with different ADs downregulate the induction of