Previously, we reported that fluoxetine acts on 5-HT receptor and induces epidermal growth factor receptor (EGFR) transactivation in astrocytes. Recently, we have found that chronic treatment with fluoxetine regulates Caveolin-1 (Cav-1)/PTEN/PI3K/AKT/glycogen synthase kinase 3β (GSK-3β) signaling pathway and glycogen content in primary cultures of astrocytes with bi-phasic concentration dependence. At low concentrations fluoxetine down-regulates Cav-1 gene expression, decreases membrane content of PTEN, increases PI3K activity and increases phosphorylation of GSK-3β and increases its activity; at high concentrations fluoxetine acts on PTEN/PI3K/AKT/GSK-3β in an inverse fashion. Here, we present the data indicating that acute treatment with fluoxetine at lower concentrations down-regulates c-Fos gene expression via PI3K/AKT signaling pathway; in contrast at higher concentrations fluoxetine up-regulates c-Fos gene expression via MAPK/extracellular-regulated kinase (ERK) signaling pathway. However, acute treatment with fluoxetine has no effect on Cav-1 protein content. Similarly, chronic effects of fluoxetine on Cav-1 gene expression are suppressed by inhibitor of PI3K at lower concentrations, but by inhibitor of MAPK at higher concentrations, indicating that the mechanism underlying bi-phasic regulation of Cav-1 gene expression by fluoxetine is opposing effects of PI3K/AKT and MAPK/ERK signal pathways on c-Fos gene expression. The effects of fluoxetine on Cav-1 gene expression at both lower and higher concentrations are abolished by AG1478, an inhibitor of EGFR, indicating the involvement of 5-HT receptor induced EGFR transactivation as we reported previously. However, PP1, an inhibitor of Src only abolished the effect by lower concentrations, suggesting the relevance of Src with PI3K/AKT signal pathway during activation of EGFR.