Glover M E, Pugh P C, Jackson N L, Cohen J L, Fant A D, Akil H, Clinton S M
Department of Psychiatry and Behavioral Neurobiology, University of Alabama-Birmingham, USA.
Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, USA.
Neuroscience. 2015 Jan 22;284:775-797. doi: 10.1016/j.neuroscience.2014.10.044. Epub 2014 Nov 4.
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.
选择性5-羟色胺再摄取抑制剂（SSRI）类抗抑郁药是治疗10%-20%患有重度抑郁症的孕期及产后女性的主要药物，但人们对SSRI类药物对其子女发育中大脑及后期情绪健康的影响知之甚少。孕期使用SSRI可引发新生儿抗抑郁药戒断反应，并增加幼儿的焦虑及社交回避行为。在啮齿动物中，围产期暴露于SSRI会增加成年动物的抑郁样和焦虑样行为，尽管某些个体比其他个体更容易受到这些影响。我们的研究利用选择性培育的低反应（bLR）和高反应（bHR）大鼠建立了一个围产期暴露于SSRI易感性个体差异的啮齿动物模型，这些大鼠先前是根据对新奇事物的行为反应高低进行培育的。怀孕的bHR/bLR雌性大鼠长期接受SSRI帕罗西汀（10毫克/千克/天，口服）治疗，以研究其对后代情绪行为及发育中大脑基因表达的影响。帕罗西汀治疗对bHR/bLR母鼠的妊娠结局或母性行为影响极小。我们发现，天生倾向于抑制/焦虑性情的bLR后代易受围产期暴露于SSRI相关行为异常的影响（这加剧了它们在强迫游泳试验中的不动时间），而高冒险性的bHR后代则具有抗性。微阵列研究显示，围产期SSRI在发育中的bLR海马体和杏仁核（出生后第7-21天）中诱导了强烈的基因表达变化，包括参与神经发生、突触小泡成分和能量代谢的转录本。这些结果突出了bLR/bHR模型作为探索围产期暴露于SSRI易感性个体差异神经生物学的有用工具。
