Antipsychotic-induced vacuous chewing movements and extrapyramidal side effects are highly heritable in mice
Antipsychotic-induced vacuous chewing movements and extrapyramidal side effects are highly heritable in mice
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DOI：
10.1038/tpj.2010.82
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发表时间：
2012-04-01
影响因子：
2.8
通讯作者：
Sullivan, P. F.
中科院分区：
文献类型：
--
作者：
Crowley, J. J.;Adkins, D. E.;Sullivan, P. F.
药物基因组学尚未兑现其明显改变临床医学的承诺。例如，迟发性运动障碍(TD)(一种因服用抗精神病药物而产生的不良药物反应)的预测测试可以极大地改善精神分裂症的临床治疗，但人类研究是模棱两可的。一种互补的方法是老鼠然后人类的设计，在这种设计中，使用有效的老鼠模型来识别易感基因座，然后在人类样本中进行测试。我们使用近亲交配的小鼠品系来评估氟哌啶醇诱导的活性和口腔表型的遗传力。总共，来自27个近交系的159只小鼠接受了氟哌啶醇(每天3 mg kg(-1)皮下缓释丸)的长期治疗，并监测了空腹咀嚼运动(VCms；小鼠类似TD)的发展以及来自开场活动和斜屏试验的其他运动表型。测试电池分别在0、30、60、90和120天与氟哌啶醇接触进行评估。正如预期的那样，氟哌啶醇引起VCM、旷场活动和锥体外系症状(EPS)的显著变化。出乎意料的是，因子分析表明，这些测量是对潜在结构的不准确评估，而不是离散结构。在纳入设计的纵向性质后，复合表型的遗传力类似于0.9。小鼠VCM是一种表面上有效的抗精神病药物诱发TD的动物模型，本研究的遗传度估计支持VCM易感基因座定位的可行性。药物基因组学杂志(2012年)12期，第147-155期；doi：10.1038/tpj.2010.82；2010年11月16日在线发布
Pharmacogenomics is yet to fulfill its promise of manifestly altering clinical medicine. As one example, a predictive test for tardive dyskinesia (TD) (an adverse drug reaction consequent to antipsychotic exposure) could greatly improve the clinical treatment of schizophrenia but human studies are equivocal. A complementary approach is the mouse-then-human design in which a valid mouse model is used to identify susceptibility loci, which are subsequently tested in human samples. We used inbred mouse strains from the Mouse Phenome Project to estimate the heritability of haloperidol-induced activity and orofacial phenotypes. In all, 159 mice from 27 inbred strains were chronically treated with haloperidol (3 mg kg(-1) per day via subdermal slow-release pellets) and monitored for the development of vacuous chewing movements (VCMs; the mouse analog of TD) and other movement phenotypes derived from open-field activity and the inclined screen test. The test battery was assessed at 0, 30, 60, 90 and 120 days in relation to haloperidol exposure. As expected, haloperidol caused marked changes in VCMs, activity in the open field and extrapyramidal symptoms (EPS). Unexpectedly, factor analysis demonstrated that these measures were imprecise assessments of a latent construct rather than discrete constructs. The heritability of a composite phenotype was similar to 0.9 after incorporation of the longitudinal nature of the design. Murine VCMs are a face valid animal model of antipsychotic-induced TD, and heritability estimates from this study support the feasibility of mapping of susceptibility loci for VCMs. The Pharmacogenomics Journal (2012) 12, 147-155; doi: 10.1038/tpj.2010.82; published online 16 November 2010