Department of Genetics, University of North Carolina, Chapel Hill, NC 27599-7264, USA.
Pharmacogenomics J. 2012 Apr;12(2):147-55. doi: 10.1038/tpj.2010.82. Epub 2010 Nov 16.
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 ∼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.
药物基因组学尚未实现其明显改变临床医学的承诺。例如，迟发性运动障碍（TD）（抗精神病药物暴露后的不良反应）的预测测试可以极大地改善精神分裂症的临床治疗，但人体研究结果存在争议。一种补充方法是“小鼠-然后人类”设计，其中使用有效的小鼠模型来识别易感基因座，然后在人类样本中进行测试。我们使用来自 Mouse Phenome Project 的近交系小鼠品系来估计氟哌啶醇诱导的活动和口面部表型的遗传性。总共，来自 27 个近交系的 159 只小鼠接受氟哌啶醇（每天通过皮下缓释微球 3mg/kg）慢性治疗，并监测空咀嚼运动（VCM；TD 的小鼠模拟物）和其他源自开放场活动和倾斜屏幕测试的运动表型的发展。在与氟哌啶醇暴露相关的 0、30、60、90 和 120 天评估测试电池。正如预期的那样，氟哌啶醇导致 VCM、开放场中的活动和锥体外系症状（EPS）发生明显变化。出乎意料的是，因子分析表明，这些措施是对潜在结构的不精确评估，而不是离散结构。在纳入设计的纵向性质后，复合表型的遗传率约为 0.9。小鼠 VCM 是一种对抗精神病药诱导的 TD 具有面部有效性的动物模型，这项研究的遗传率估计支持 VCM 易感基因座图谱的可行性。
