Early-life exposure to the SSRI paroxetine exacerbates depression-like behavior in anxiety/depression-prone rats

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.

Differential stress induced c-Fos expression and identification of region-specific miRNA-mRNA networks in the dorsal raphe and amygdala of high-responder/low-responder rats

“…Our group and others previously reported HR/LR differences in behavioral despair [14], aggression [15], and anxiety-like behavior [13]. These differences suggested that HR rats display a proactive coping style while LRs display a reactive coping style.…”

“…Rats bred for high response to novelty (High Responders, HRs) vigorously explore new environments compared to rats bred for low novelty response (Low Responders, LRs). Selective breeding produced rats with differences in anxiety/depression-like behavior, with LR rats displaying high and HR rats displaying low anxiety/depression-like behavior as measured by the forced swim test (FST) [14], resident-intruder test [15], and elevated plus maze [13]. These behavioral differences suggest that HRs display proactive coping across several tests while LRs display reactive coping.…”

“…LRs also show higher 5HT1a receptor mRNA levels in the cingulate, lateral septum, and CA1 region of the hippocampus, compared to HRs [30], as well as increased 5HT2a [22], 5HT6 and 5HT7 [31] receptor mRNA in multiple forebrain regions. Pharmacological studies suggest that HR/LR 5HT differences shape aspects of their disparate behavioral phenotypes, including differences in FST performance [14], social interaction [22, 32], aggression [15, 30], cognition [31], reward-processing [33], and anxiety [34]. …”

Altered metabolic activity in the developing brain of rats predisposed to high versus low depression-like behavior

“…RNA samples from the HR and LR P7/P14/P21 hippocampus, amygdala, and prefrontal cortex (n=5 samples/group) were shipped on dry ice for genome-wide expression profiling using NimbleGen Rat Gene Expression 12×135 Arrays (26,419 target genes, 5 probes/targets; Arraystar, Rockville, MD) as previously described (Glover et al, 2015). Briefly, RNA quality and quantity were assessed with Nanodrop ND-1000 (Thermo Scientific, Wilmington, DE) and the RNA integrity was evaluated through denaturing agarose gel electrophoresis.…”

Antenatal depression, treatment with selective serotonin reuptake inhibitors, and neonatal brain structure: A propensity-matched cohort study

“…In rodents, exposure to SSRIs in the prenatal and/or early neonatal period disrupts dendritic organization and formation of thalamocortical afferents to the somatosensory cortex and results in aberrant axonal morphology, abnormal raphe circuitry, and altered cortical function (Lee, 2009; Liao and Lee, 2011; Simpson et al, 2011; Xu et al, 2004). These changes are accompanied by behavioral disturbances including decreased exploratory behavior and increased emotional reactivity, altered social behavior, and impaired motor performance (Borue et al, 2007; Glover et al, 2015; Xu et al, 2004). …”