Perinatal paroxetine exposure in Selcetively-bred Low Responder rats

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 (LR) and High Responder (HR) rats that were previously bred for high versus low behavioral response to novelty. Pregnant HR/LR 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 HR/LR dams’ pregnancy outcomes or maternal behavior. We found that LR 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 HR offspring were resistant. Microarray studies revealed robust perinatal SSRI-induced gene expression changes in the developing LR hippocampus and amygdala (postnatal days 7-21), including transcripts involved in neurogenesis, synaptic vesicle components, and energy metabolism. These results highlight the LR/HR model as a useful tool to explore the neurobiology of individual differences in susceptibility to perinatal SSRI exposure.选择性5-羟色胺再摄取抑制剂 (Selective serotonin reuptake inhibitor, SSRI) 类抗抑郁药是10%~20%罹患重度抑郁症的妊娠及产后女性的主流治疗手段，但目前学界对SSRI对子代大脑发育及后续情绪健康的影响仍知之甚少。妊娠期使用SSRI可引发新生儿抗抑郁药戒断反应，并增加幼儿的焦虑与社交回避行为。在啮齿类动物实验中，围产期SSRI暴露会增加成年个体的抑郁样与焦虑样行为，但不同个体对这类影响的易感性存在差异。本研究利用此前为筛选对新奇环境的行为反应高低而选育的低反应者 (Low Responder, LR) 与高反应者 (High Responder, HR) 大鼠，构建了围产期SSRI暴露易感性个体差异的啮齿类动物模型。对妊娠HR及LR雌鼠长期给予SSRI类药物帕罗西汀 (paroxetine)（10 mg/kg/天，p.o.），以探究其对子代情绪行为及发育中大脑基因表达的影响。帕罗西汀给药对HR及LR母鼠的妊娠结局或母性行为影响极小。研究发现，天生倾向于抑制型/焦虑型气质的LR子代，更易出现与围产期SSRI暴露相关的行为异常，该暴露会加重其强迫游泳实验 (Forced Swim Test) 中的不动时间，而天生高风险偏好的HR子代则表现出抗性。基因芯片 (Microarray) 分析结果显示，围产期SSRI暴露可使发育中LR子代的海马体 (hippocampus) 与杏仁核 (amygdala)（出生后第7至21天）产生显著的基因表达变化，涉及神经发生 (neurogenesis)、突触囊泡 (synaptic vesicle) 组分及能量代谢 (energy metabolism) 相关的转录本。上述研究结果表明，LR/HR模型可作为探究围产期SSRI暴露易感性个体差异神经生物学机制的有效工具。