A common mechanism of action of the selective serotonin reuptake inhibitors citalopram and fluoxetine: reversal of chronic psychosocial stress-induced increase in CRE/CREB-directed gene transcription in transgenic reporter gene mice.
The transcription factor CREB regulates adaptive responses like memory consolidation, addiction, and synaptic refinement. Recently, chronic psychosocial stress as animal model of depression has been shown to stimulate CREB transcriptional activity in the brain; this stimulation was prevented by treatment with the antidepressant imipramine, which inhibits both noradrenaline and serotonin reuptake. However, it was unknown whether the selective inhibition of serotonin reuptake is sufficient for inhibition of stress-induced CREB activation, as it is for the clinical antidepressant effect. Therefore, the effect of two selective serotonin reuptake inhibitors (SSRIs), citalopram and fluoxetine, was examined in this study. Transgenic CRE-luciferase reporter gene mice were used to monitor gene transcription directed by the CREB DNA binding site (CRE) in vivo. Chronic psychosocial stress for 25days stimulated CRE/CREB-directed luciferase expression in the hippocampus and other brain regions. When applied alone to non-stressed mice, citalopram caused a transient increase after 24h that was lost after 21days of treatment, whereas fluoxetine had no effect after 24h and produced an inhibition in the pons and hypothalamus after 21days of treatment. However, both citalopram and fluoxetine treatment completely abolished the increase in CRE/CREB-directed transcription induced by chronic psychosocial stress. As indicated by Western blots, the changes in CRE/CREB-directed transcription were accompanied by corresponding changes in the phosphorylation of CREB at serine-119. These results further emphasize the role of CREB in stress-induced gene expression and suggest furthermore that inhibition of stress-induced CREB activity may be a common mechanism of action of SSRIs underlying their antidepressive effect.
Böer
Ulrike
U
Department of Molecular Pharmacology, University of Göttingen, Robert-Koch-Str. 40, 37099 Göttingen, Germany. ulrike.boeer@gmx.de
Noll
Christine
C
Cierny
Irmgard
I
Krause
Doris
D
Hiemke
Christoph
C
Knepel
Willhart
W
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D015283:Citalopram / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004334:Drug Administration Schedule; D005473:Fluoxetine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D013315:Stress, Psychological / Q000188:drug therapy* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*
D015283:Citalopram; D017362:Cyclic AMP Response Element-Binding Protein; D005473:Fluoxetine; D017367:Selective Serotonin Reuptake Inhibitors