In well-differentiated primary cultures of mouse astrocytes, which express no serotonin transporter (SERT), the ‘serotonin-specific reuptake inhibitor’ (SSRI) fluoxetine leads acutely to 5-HT_2B receptor-mediated, transactivation-dependent phosphorylation of extracellular regulated kinases 1/2 (ERK_1/2) with an EC₅₀ of ~5 μM, and chronically to ERK_1/2 phosphorylation-dependent upregulation of mRNA and protein expression of calcium-dependent phospholipase A₂ (cPLA₂) with ten-fold higher affinity. This affinity is high enough that fluoxetine given therapeutically may activate astrocytic 5-HT_2B receptors (Li et al., 2008, 2009). We now confirm the expression of 5-HT_2B receptors in astrocytes freshly dissociated from mouse brain and isolated by fluorescence-activated cell sorting (FACS) and investigate in cultured cells if the effects of fluoxetine are shared by all five conventional SSRIs with sufficiently high affinity to be relevant for mechanism(s) of action of SSRIs. Phosphorylated and total ERK_1/2 and mRNA and protein expression of cPLA_2a were determined by Western blot and reverse transcription polymerase chain reaction (RT-PCR). Paroxetine, which differs widely from fluoxetine in affinity for SERT and for another 5-HT₂ receptor, the 5-HT_2C receptor, acted acutely and chronically like fluoxetine. One micromolar of paroxetine, fluvoxamine or sertraline increased cPLA_2a expression during chronic treatment; citalopram had a similar effect at 0.1–0.5 μM; these are therapeutically relevant concentrations.