INSERM U862, Avenir group Physiopathology of Energy Balance and Obesity, Université de Bordeaux 2, Bordeaux, France.
Pharmacogenet Genomics. 2011 Dec;21(12):779-89. doi: 10.1097/FPC.0b013e32834b3f35.
Selecting an effective treatment for patients with major depressive disorder is a perpetual problem for psychiatrists. It is of particular interest to explore the interaction between genetic predisposition and environmental factors.
Mouse inbred strains vary in baseline performance in depression-related behaviour tests, which were originally validated as tests of antidepressant response. Therefore, we investigated interactions between environmental stress, genotype, and drug response in a multifactorial behaviour study.
Our study design included four inbred mouse strains (129S1/SvlmJ, C57LB/6J, DBA/2J and FVB/NJ) of both sexes, two subjected to environmental manipulations (maternal separation and unpredictable chronic mild stress) and two representative of treatment with antidepressants (escitalopram and nortryptiline vs. vehicle). The mice treated with antidepressants were further divided into those administered acute (1 day) and subchronic (14 days) regimes, giving 144 experimental groups in all, each with at least seven animals. All animals were tested using the Porsolt forced-swim test (FST) and the hole-board test.
Despite a 24-h maternal separation (MS) or a 14-day unpredictable chronic mild stress protocol, most animals seemed to be resilient to the stress induced. One compelling finding is the long-lasting, strain-specific effect of MS resulting in an increased depression-like behaviour in the Porsolt FST and elevated anxiety-related behaviour in the hole-board test seen in 129S1/SvImJ mice. Nortriptyline was effective in reversing the effect of MS in the FST in 129S1/SvlmJ male mice.
A single 24-h maternal separation of pups from their mother on postnatal day 9 is a sufficient insult to result in a depression-like phenotype in adult 129S1/SvImJ mice but not in C57LB/6 J, DBA/2 J, and FVB/NJ mice.
为患有重度抑郁症的患者选择有效的治疗方法是精神科医生面临的一个长期问题。探索遗传易感性和环境因素之间的相互作用尤其具有意义。
在与抑郁相关的行为测试中，不同品系的小鼠在基线表现上存在差异，这些测试最初被验证为抗抑郁反应测试。因此，我们在一项多因素行为研究中调查了环境应激、基因型和药物反应之间的相互作用。
我们的研究设计包括四个不同品系（129S1/SvlmJ、C57LB/6J、DBA/2J 和 FVB/NJ）的雌雄小鼠，其中两个品系接受环境操作（母婴分离和不可预测的慢性轻度应激），两个品系接受抗抑郁药物治疗（艾司西酞普兰和去甲替林与载体）。接受抗抑郁药物治疗的小鼠进一步分为接受急性（1 天）和亚慢性（14 天）治疗方案的小鼠，总共包括 144 个实验组，每个组至少有 7 只动物。所有动物均接受强迫游泳试验（FST）和洞板试验检测。
尽管进行了 24 小时母婴分离（MS）或 14 天不可预测的慢性轻度应激处理，但大多数动物似乎对诱导的应激具有抵抗力。一个引人注目的发现是，MS 具有持久的、特定于品系的效应，导致 129S1/SvImJ 小鼠在 Porsolt FST 中表现出抑郁样行为增加，在洞板试验中表现出焦虑样行为增加。去甲替林可有效逆转 129S1/SvlmJ 雄性小鼠 FST 中 MS 的作用。
新生后第 9 天对幼鼠进行单次 24 小时母婴分离足以导致成年 129S1/SvImJ 小鼠出现抑郁表型，但对 C57LB/6J、DBA/2J 和 FVB/NJ 小鼠则无此作用。
