Article

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

ABSTRACT

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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    • "Specifically, subchronic (under 20 days) exposure to fluoxetine has no effect on time spent in the light compartment (Ihne et al. 2012;Lesemann et al. 2012), while chronic (over 20 days) exposure has been reported to both increase (Ihne et al. 2012) and decrease time spent in the light compartment of the light/dark box (Vicente and Zangrossi 2014). Curiously, acute and chronic (e.g., 28 days) treatment with paroxetine decreases anxiety-like behavior in adult rodents (Hascoët et al. 2000;Sillaber et al. 2008). Age-dependent differences in the action of paroxetine are of potential importance because SSRI-induced increases in anxiety-like behavior raise the risk of suicidal behavior in adolescent humans (Hawgood and De Leo 2008;Sareen 2011). "
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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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