title: Effects of chronic treatment with fluoxetine on receptor-stimulated increase of [Ca2+]i in astrocytes mimic those of acute inhibition of TRPC1 channel activity.
abstract: Primary cultures of mouse astrocytes were used to investigate effects by chronic treatment (3-21 days) with fluoxetine (0.5-10 μM) on capacitative Ca(2+) influx after treatment with the SERCA inhibitor thapsigargin and on receptor agonist-induced increases in free cytosolic Ca(2+) concentration [Ca(2+)](i), determined with Fura-2. The agonists were the 5-HT(2B) agonist fluoxetine, the α(2)-adrenergic agonist dexmedetomidine, and ryanodine receptor (RyR) and IP(3) receptor (IP(3)R) agonists. In untreated sister cultures each agonist distinctly increased [Ca(2+)](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 IP(3)R agonists elicited reduced, in some cases abolished, effects. Capacitative Ca(2+) entry, meditated by TRPC1 channels, was sufficiently inhibited to cause a depletion of Ca(2+) 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 [Ca(2+)](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).
authors.affiliation: Department of Clinical Pharmacology, China Medical University, Shenyang, PR China.
authors.forename: Baoman
authors.initials: B
authors.lastname: Li
authors.forename: Lu
authors.initials: L
authors.lastname: Dong
authors.forename: Hui
authors.initials: H
authors.lastname: Fu
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.forename: Leif
authors.initials: L
authors.lastname: Hertz
authors.forename: Liang
authors.initials: L
authors.lastname: Peng
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D005473:Fluoxetine / Q000494:pharmacology*; D016257:Fura-2 / Q000494:pharmacology; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000819:agonists / Q000378:metabolism; D051379:Mice; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000737:chemistry / Q000378:metabolism; D044348:Receptors, Serotonin, 5-HT2 / Q000737:chemistry / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D002118:Calcium; D005473:Fluoxetine; D016257:Fura-2; D053496:Inositol 1,4,5-Trisphosphate Receptors; D034741:RNA, Small Interfering; D018341:Receptors, Adrenergic, alpha-2; D044348:Receptors, Serotonin, 5-HT2; D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D017367:Selective Serotonin Reuptake Inhibitors; D050052:TRPC Cation Channels; D019284:Thapsigargin; C096351:transient receptor potential cation channel, subfamily C, member 1