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.

Download full-text


Available from: Marcelo Paez-Pereda
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The SSRI antidepressant fluoxetine is one of the few drugs that is effective at treating depression in adolescent humans. In contrast, the SSRI paroxetine has limited efficacy and is more at risk for inducing suicidal behavior. The purpose of the present study was to more fully characterize the differential actions of paroxetine and fluoxetine. In experiment 1, male and female rats were injected with paroxetine (2.5 or 10 mg/kg), fluoxetine (10 mg/kg), or vehicle for 10 days starting on postnatal day (PD) 35, and affective behaviors were assessed using sucrose preference and elevated plus maze tasks. A separate set of rats were used to examine monoamine levels. In experiment 2, rats were injected with paroxetine (2.5, 5, or 10 mg/kg), fluoxetine (5, 10, or 20 mg/kg), or vehicle during the same time frame as experiment 1, and anxiety-like behaviors were measured using elevated plus maze, light/dark box, and acoustic startle. Repeated SSRI treatment failed to alter sucrose preference, although both paroxetine and fluoxetine reduced time spent in the open arms of the elevated plus maze and light compartment of the light/dark box. Paroxetine, but not fluoxetine, enhanced acoustic startle and interfered with habituation. Serotonin turnover was decreased by both acute and repeated fluoxetine treatment but unaltered by paroxetine administration. These results show that repeated treatment with paroxetine and fluoxetine has dissociable actions in adolescent rats. In particular, paroxetine, but not fluoxetine, increases acoustic startle at low doses and may increase sensitivity to environmental stressors.
    Preview · Article · Jul 2015 · Psychopharmacology
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Selective serotonin reuptake inhibitor (SSRI) antidepressants are the mainstay treatment for the 10–20% of pregnant and postpartum women who suffer major depression, but the effects of SSRIs on their children’s developing brain and later emotional health are poorly understood. SSRI use during pregnancy can elicit antidepressant withdrawal in newborns and increase toddlers’ anxiety and social avoidance. In rodents, perinatal SSRI exposure increases adult depression- and anxiety-like behavior, although certain individuals are more vulnerable to these effects than others. Our study establishes a rodent model of individual differences in susceptibility to perinatal SSRI exposure, utilizing selectively bred Low Responder (bLR) and High Responder (bHR) rats that were previously bred for high versus low behavioral response to novelty. Pregnant bHR/bLR females were chronically treated with the SSRI paroxetine (10 mg/kg/day p.o.) to examine its effects on offspring’s emotional behavior and gene expression in the developing brain. Paroxetine treatment had minimal effect on bHR/bLR dams’ pregnancy outcomes or maternal behavior. We found that bLR offspring, naturally prone to an inhibited/anxious temperament, were susceptible to behavioral abnormalities associated with perinatal SSRI exposure (which exacerbated their Forced Swim Test immobility), while high risk-taking bHR offspring were resistant. Microarray studies revealed robust perinatal SSRI-induced gene expression changes in the developing bLR hippocampus and amygdala (postnatal days 7–21), including transcripts involved in neurogenesis, synaptic vesicle components, and energy metabolism. These results highlight the bLR/bHR model as a useful tool to explore the neurobiology of individual differences in susceptibility to perinatal SSRI exposure.
    Full-text · Article · Nov 2014 · Neuroscience
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: MDMA (3,4-methylenedioxymethamphetamine) is a substituted amphetamine and popular drug of abuse. Its mood-enhancing short-term effects may prompt its consumption under stress. Clinical studies indicate that MDMA treatment may mitigate the symptoms of stress disorders such as posttraumatic stress syndrome (PTSD). On the other hand, repeated administration of MDMA results in persistent deficits in markers of serotonergic (5-HT) nerve terminals that have been viewed as indicative of 5-HT neurotoxicity. Exposure to chronic stress has been shown to augment MDMA-induced 5-HT neurotoxicity. Here, we examine the transcriptional responses in the hippocampus to MDMA treatment of control rats and rats exposed to chronic stress. MDMA altered the expression of genes that regulate unfolded protein binding, protein folding, calmodulin-dependent protein kinase activity, and neuropeptide signaling. In stressed rats, the gene expression profile in response to MDMA was altered to affect sensory processing and responses to tissue damage in nerve sheaths. Subsequent treatment with MDMA also markedly altered the genetic responses to stress such that the stress-induced downregulation of genes related to the circadian rhythm was reversed. The data support the view that MDMA-induced transcriptional responses accompany the persistent effects of this drug on neuronal structure/function. In addition, MDMA treatment alters the stress-induced transcriptional signature.
    Full-text · Article · Jan 2014
Show more