Schizophrenia is an idiopathic disorder that affects approximately 1% of the human population, and presents with persistent delusions, hallucinations, and disorganized behaviors. Antipsychotics are the standard pharmacological treatment for schizophrenia, but are frequently discontinued by patients due to inefficacy and/or side effects. Chronic treatment with the typical antipsychotic haloperidol causes tardive dyskinesia (TD), which manifests as involuntary and often irreversible orofacial movements in around 30% of patients. Mice treated with haloperidol develop many of the features of TD, including jaw tremors, tongue protrusions, and vacuous chewing movements (VCMs). In this study, we used genetically diverse Collaborative Cross (CC) recombinant inbred inter-cross (RIX) mice to elucidate the genetic basis of antipsychotic-induced adverse drug reactions (ADRs). We performed a battery of behavioral tests in 840 mice from 73 RIX lines (derived from 62 CC strains) treated with haloperidol or placebo in order to monitor the development of ADRs. We used linear mixed models to test for strain and treatment effects. We observed highly significant strain effects for almost all behavioral measurements investigated (P < 0.001). Further, we observed strong strain-by-treatment interactions for most phenotypes, particularly for changes in distance traveled, vertical activity, and extrapyramidal symptoms (EPS). Estimates of overall heritability ranged from 0.21 (change in body weight) to 0.4 (VCMs and change in distance traveled) while the portion attributable to the interactions of treatment and strain ranged from 0.01 (for change in body weight) to 0.15 (for change in EPS). Interestingly, close to 30% of RIX mice exhibited VCMs, a sensitivity to haloperidol exposure, approximately similar to the rate of TD in humans chronically exposed to haloperidol. Understanding the genetic basis for the susceptibility to antipsychotic ADRs may be possible in mouse, and extrapolation to humans could lead to safer therapeutic approaches for schizophrenia.

精神分裂症是一种特发性疾病，影响大约 1% 的人口，并表现为持续的妄想、幻觉和行为紊乱。抗精神病药是精神分裂症的标准药物治疗，但由于无效和/或副作用经常被患者停用。用典型的抗精神病药氟哌啶醇长期治疗会导致迟发性运动障碍 (TD)，约 30% 的患者表现为不自主且通常不可逆的口面部运动。用氟哌啶醇治疗的小鼠会出现 TD 的许多特征，包括下巴震颤、舌头突出和空洞咀嚼运动 (VCM)。在这项研究中，我们使用遗传多样性的协作杂交 (CC) 重组近交杂交 (RIX) 小鼠来阐明抗精神病药引起的药物不良反应 (ADR) 的遗传基础。我们对来自 73 个 RIX 品系（来自 62 个 CC 品系）的 840 只小鼠进行了一系列行为测试，这些小鼠用氟哌啶醇或安慰剂治疗，以监测 ADR 的发展。我们使用线性混合模型来测试应变和治疗效果。对于几乎所有调查的行为测量，我们都观察到了非常显着的应变效应（磷< 0.001)。此外，我们观察到大多数表型的强烈应变与治疗相互作用，特别是对于行进距离、垂直活动和锥体外系症状 (EPS) 的变化。整体遗传力的估计范围从 0.21（体重变化）到 0.4（VCM 和行进距离变化），而归因于治疗和应变相互作用的部分范围从 0.01（体重变化）到 0.15（体重变化）每股收益）。有趣的是，接近 30% 的 RIX 小鼠表现出 VCM，这是一种对氟哌啶醇暴露的敏感性，与长期暴露于氟哌啶醇的人类的 TD 率大致相似。在小鼠中了解抗精神病药物 ADR 易感性的遗传基础可能是可能的，外推到人类可能会导致更安全的精神分裂症治疗方法。