Profiling of behavioral changes and hippocampal gene expression in mice chronically treated with the SSRI paroxetine

Max-Planck-Institute of Psychiatry, 80804 Munich, Germany.
Psychopharmacology (Impact Factor: 3.88). 11/2008; 200(4):557-72. DOI: 10.1007/s00213-008-1232-6
Source: OAI


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

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Available from: Marcelo Paez-Pereda,
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    • "The paroxetine solutions were renewed every 2 days, and drug concentrations were calculated according to body weight and water intake of each rat, determined by weighing the drinking bottles at each renewal. The 10 mg/kg/day dose was selected based on previous literature showing antidepressant and neurochemical effects of paroxetine in adult rats (Carlson et al., 1996; Sillaber et al., 2008). In addition, oral administration of paroxetine at this dose to adolescent and adult rats was previously shown to produce drug plasma concentrations that approximate human therapeutic concentrations (10–600 ng/ml) (DeVane, 1999; Karanges et al., 2013). "
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    • "Genes with í µí±ƒ value < 0.05, absolute fold change > 1.2, and average intensity > 100 fluorescent units were considered significantly differentially expressed. These cutoffs are consistent with similar studies in the literature [34] [35] [36] [37]. Significant genes were further analyzed by Fisher's exact tests to identify overrepresented gene ontology categories and KEGG pathways. "
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    • "This elevation in adverse effects in adolescents is present despite substantially lower, although still therapeutically relevant (DeVane, 1999) plasma PRX in adolescents compared to adults. Although several previous studies have investigated proteomic changes in adult rodents or neural cell cultures following the administration of PRX and other SSRIs (e.g., McHugh et al., 2008, 2010; Sillaber et al., 2008), this is the first study to our knowledge that has examined changes occurring in the adolescent brain. We provide evidence that chronic PRX treatment produces differential, although overlapping, changes in the hippocampal proteome in adolescent rats compared to adults, and these changes can be linked to the regulation of neurotransmitter function, major signaling pathways, cell proliferation and death, oxidative stress, and cytoskeleton structure. "
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