Selective serotonin reuptake inhibitors and raft inhibitors shorten the period of Period1-driven circadian bioluminescence rhythms in rat-1 fibroblasts.
Alterations in circadian rhythm generation may be related to the development of mood disorders. Although it has been reported that the most popular antidepressant, selective serotonin reuptake inhibitors (SSRIs) affect circadian phase, no data are available that describe the effects of SSRIs on other circadian parameters (period, amplitude and damping rate) in dissociated cells. In the present study we used real-time monitoring of bioluminescence in rat-1 fibroblasts expressing the Period1-luciferase transgene, and that in Period1-luciferase transgenic mouse suprachiasmatic nucleus (SCN) explants, in order to characterize the effects of SSRI on circadian oscillator function in vitro. We found that mRNA of the serotonin transporter (SERT), a target of SSRIs, was expressed in rat-1 fibroblasts. Sertraline, fluoxetine, fluvoxamine, citalopram and paroxetine all significantly shortened the period of Period1-bioluminescence rhythms in rat-1 fibroblasts. The amplitude was reduced by sertraline, and the damping rate was decreased by sertraline, fluoxetine, flvoxamine and paroxetine. The effect of sertraline was dose-dependent, and it also shortened the circadian period in the SCN. SERT is associated with lipid microdomains, which are required for efficient SERT activity. Indeed, cholesterol chelating reagent methyl-beta-cyclodextrin significantly reduced the period and the amplitude in rat-1 fibroblasts. Furthermore, lipid binding reagent xylazine significantly reduced the period. In summary our data present evidence that SSRIs affect circadian rhythmicity. The action of SSRIs is likely mediated by suppression of SERT activity. A better understanding of the relationship between mental illness and biological timing may yield new insight into disease etiology and avenues for treatment.
Nomura
Kazumi
K
Circadian Rhythms and Sleep Disorders Program, Neuroscience Institute, Department of Anatomy and Neurobiology, Morehouse School of Medicine, Atlanta, GA 30310-1495, USA.
Castanon-Cervantes
Oscar
O
Davidson
Alec
A
Fukuhara
Chiaki
C
D000818:Animals; D002940:Circadian Rhythm / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D017930:Genes, Reporter; D066298:In Vitro Techniques; D008156:Luciferases / Q000235:genetics; D008297:Male; D021962:Membrane Microdomains / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D056950:Period Circadian Proteins; D051381:Rats; D050486:Serotonin Plasma Membrane Transport Proteins / Q000096:biosynthesis; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013493:Suprachiasmatic Nucleus / Q000187:drug effects* / Q000378:metabolism; D014162:Transfection
D005136:Eye Proteins; D008156:Luciferases; D056950:Period Circadian Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C539023:Per1 protein, mouse; C539024:Per1 protein, rat