Profiling of behavioral changes and hippocampal gene expression in mice chronically treated with the SSRI paroxetine.
BACKGROUND
Monoamine-based antidepressants inhibit neurotransmitter reuptake within short time. However, it commonly takes several weeks until clinical symptoms start to resolve--indicating the involvement of effects distant from reuptake inhibition.


OBJECTIVE
To unravel other mechanisms involved in drug action, a "reverse" pharmacological approach was applied to determine antidepressant-induced alterations of hippocampal gene expression.


METHODS
The behavioral response to long-term paroxetine administration of male DBA/2Ola mice was assessed by the forced swim test (FST), the modified hole board (mHB), and the dark/light box. Hippocampi of test-naive mice were dissected, and changes in gene expression by paroxetine treatment were investigated by means of microarray technology.


CONCLUSIONS
Robust effects of paroxetine on passive stress-coping behavior in the FST were observed. Furthermore, anxiolytic properties of long-term antidepressant treatment could be identified in DBA mice in both, the mHB and dark/light box. Analysis of microarray results revealed a list of 60 genes differentially regulated by chronic paroxetine treatment. Preproenkephalin 1 and inhibin beta-A showed the highest level of transcriptional change. Furthermore, a number of candidates involved in neuroplasticity/neurogenesis emerged (e.g., Bdnf, Gfap, Vim, Sox11, Egr1, Stat3). Seven selected candidates were confirmed by in situ hybridization. Additional immunofluorescence colocalization studies of GFAP and vimentin showed more positive cells to be detected in long-term paroxetine-treated DBA mice.


CONCLUSIONS
Candidate genes identified in the current study using a mouse strain validated for its responsiveness to long-term paroxetine treatment add, in our opinion, to unraveling the mechanism of action of paroxetine as a representative for SSRIs.
Sillaber
Inge
I
Max-Planck-Institute of Psychiatry, 80804 Munich, Germany. sillaber@affectis.com
Panhuysen
Markus
M
Henniger
Markus S H
MS
Ohl
Frauke
F
Kühne
Claudia
C
Pütz
Benno
B
Pohl
Thomas
T
Deussing
Jan M
JM
Paez-Pereda
Marcelo
M
Holsboer
Florian
F
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D003624:Darkness; D003863:Depression / Q000188:drug therapy / Q000503:physiopathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008027:Light; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D017374:Paroxetine / Q000008:administration & dosage / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D013550:Swimming
D018687:Antidepressive Agents, Second-Generation; D017374:Paroxetine; D017367:Selective Serotonin Reuptake Inhibitors