Effects of chronic treatment with fluoxetine on receptor-stimulated increase of [Ca2+]i in astrocytes mimic those of acute inhibition of TRPC1 channel activity

Primary cultures of mouse astrocytes were used to investigate effects by chronic treatment (3–21 days) with fluoxetine (0.5–10 μM) on capacitative Ca2+ influx after treatment with the SERCA inhibitor thapsigargin and on receptor agonist-induced increases in free cytosolic Ca2+ concentration [Ca2+]i, determined with Fura-2. The agonists were the 5-HT2B agonist fluoxetine, the α2-adrenergic agonist dexmedetomidine, and ryanodine receptor (RyR) and IP3 receptor (IP3R) agonists. In untreated sister cultures each agonist distinctly increased [Ca2+]i, but in cultures treated for sufficient length of time or with sufficiently high doses of fluoxetine, acute administration of fluoxetine, dexmedetomidine, or RyR or IP3R agonists elicited reduced, in some cases abolished, effects. Capacitative Ca2+ entry, meditated by TRPC1 channels, was sufficiently inhibited to cause a depletion of Ca2+ stores, which could explain the reduced agonist effects. All effects of chronic fluoxetine administration could be replicated by TRPC1 channel antibody or siRNA. Since increases in astrocytic [Ca2+]i regulate release of gliotransmitters, these effects may have profound effects on brain function. They may be important for therapeutic effects of all 5 conventional ‘serotonin-specific reuptake inhibitors’ (SSRIs), which at concentrations used therapeutically (∼1 μM) share other of fluoxetine's chronic effects (Zhang et al., Neuron Glia Biol. 16 (2010) 1–13).