Previously, we reported that fluoxetine acts on 5-HT2B receptor and induces EGF receptor transactivation in astrocytes. Recently, we have found that chronic treatment with fluoxetine regulates Cav-1/PTEN/PI3K/AKT/GSK-3β signalling 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 signalling pathway; in contrast at higher concentrations fluoxetine up-regulates c-Fos gene expression via MAPK/ERK signalling 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 EGF receptor, indicating the involvement of 5-HT2B receptor induced EGF receptor 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 EGF receptor.

Here, we report the association between depressive behavior (anhedonia) and astroglial expression of 5-hydroxytryptamine receptor 2B (5-HT_2B) in an animal model of Parkinson’s disease, induced by bilateral injection of 6-hydroxydopamine (6-OHDA) into the striatum. Expression of the 5-HT_2B receptor at the mRNA and protein level was decreased in the brain tissue of 6-OHDA-treated animals with anhedonia. Expression of the 5-HT_2B receptor was corrected by four weeks treatment with either l-3,4-dihydroxyphenylalanine (l-dopa) or fluoxetine. Simultaneously, treatment with l-dopa abolished 6-OHDA effects on both depressive behavior and motor activity. In contrast, fluoxetine corrected 6-OHDA-induced depression but did not affect 6-OHDA-induced motor deficiency. In addition, 6-OHDA downregulated gene expression of the 5-HT_2B receptor in astrocytes in purified cell culture and this downregulation was corrected by both l-dopa and fluoxetine. Our findings suggest that 6-OHDA-induced depressive behavior may be related to the downregulation of gene expression of the 5-HT_2B receptor but 6-OHDA-induced motor deficiency reflects, arguably, dopamine depletion. Previously, we demonstrated that fluoxetine regulates gene expression in astrocytes by 5-HT_2B receptor-mediated transactivation of epidermal growth factor receptor (EGFR). However, the underlying mechanism of l-dopa action remains unclear. The present work indicates that the decrease of gene expression of the astroglial 5-HT_2B receptor may contribute to development of depressive behavior in Parkinson’s disease.