Animal Models of Schizophrenia
Animal Models of Schizophrenia
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DOI：
10.1007/7854_2010_62
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发表时间：
2010-01-01
期刊：
影响因子：
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通讯作者：
Geyer, Mark A.
中科院分区：
文献类型：
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作者：
Young, Jared W.;Zhou, Xianjin;Geyer, Mark A.
精神分裂症很可能代表着人类历史上最具异质性的精神障碍之一。这种异质性包括(1)病因学；许多可能的遗传和环境因素可能导致疾病表现；(2)症状学；具有群体特征的症状；健康受试者中通常不存在的积极行为(如幻觉)、正常行为的负面表达减少(如喜悦减少)，以及可与负面症状分开的认知能力下降(如注意力受损)，以及(3)个体对治疗的反应差异。这种独特的人类疾病的复杂性使得开发合适的动物模型来测试推定的治疗方法变得复杂起来。此外，动物模型的发展还受到缺乏阳性对照的进一步限制，因为目前批准的治疗方法只针对精神病症状，只有少量的阴性症状治疗。然而，尽管有这些复杂性，许多精神分裂症的动物模型已经被开发出来，主要集中在模拟个别症状上。已经建立了验证标准来分析这些模型的实用性，确定了(1)面部、(2)预测性、(3)构造性和(4)病因效度，以及(5)重复性。其中许多模型是随着精神分裂症的主要假说的发展而建立的，包括多巴胺能、谷氨酸能和神经发育假说。前两个模型主要包括操纵这些神经递质系统来产生与精神分裂症的症状或假定病因有一定关联的行为异常。鉴于5-羟色胺能与幻觉和胆碱能与注意力的联系，其他模型也操纵了这些系统。最后，也有一种利用转基因技术创造精神分裂症小鼠模型的动力。因此，有机会将环境和遗传因素结合起来，创造出更合适的精神分裂症模型。还在创建更复杂的动物任务，以确定这些模型是否会产生与精神分裂症患者一致的行为异常。虽然精神分裂症的动物模型仍在继续发展，但我们必须认识到，(1)验证这些模型受到临床医生提供这些患者行为相关信息的程度的限制，(2)任何假定的治疗也可能与抗精神病药物治疗同时进行。虽然我们对这种毁灭性疾病的了解增加了，我们用来衡量它们行为的动物模型和任务也变得更加复杂，但在将假定的疗法引入人体试验时，在验证这些模型以限制并发症时仍然必须谨慎。
Schizophrenia may well represent one of the most heterogenous mental disorders in human history. This heterogeneity encompasses (1) etiology; where numerous putative genetic and environmental factors may contribute to disease manifestation, (2) symptomatology; with symptoms characterized by group; positive - behaviors not normally present in healthy subjects (e.g. hallucinations), negative reduced expression of normal behaviors (e.g. reduced joy), and cognitive reduced cognitive capabilities separable from negative symptoms (e.g. impaired attention), and (3) individual response variation to treatment. The complexity of this uniquely human disorder has complicated the development of suitable animal models with which to assay putative therapeutics. Moreover, the development of animal models is further limited by a lack of positive controls because currently approved therapeutics only addresses psychotic symptoms, with minor negative symptom treatment.Despite these complexities however, many animal models of schizophrenia have been developed mainly focusing on modeling individual symptoms. Validation criteria have been established to assay the utility of these models, determining the (1) face, (2) predictive, (3) construct, and (4) etiological validities, as well as (5) reproducibility of each model. Many of these models have been created following the development of major hypotheses of schizophrenia, including the dopaminergic, glutamatergic, and neurodevelopmental hypotheses. The former two models have largely consisted of manipulating these neurotransmitter systems to produce behavioral abnormalities with some relevance to symptoms or putative etiology of schizophrenia. Given the serotonergic link to hallucinations and cholinergic link to attention, other models have manipulated these systems also. Finally, there has also been a drive toward creating mouse models of schizophrenia utilizing transgenic technology. Thus, there are opportunities to combine both environmental and genetic factors to create more suitable models of schizophrenia. More sophisticated animal tasks are also being created with which to ascertain whether these models produce behavioral abnormalities consistent with patients with schizophrenia.While animal models of schizophrenia continue to be developed, we must be cognizant that (1) validating these models are limited to the degree by which Clinicians can provide relevant information on the behavior of these patients, and (2) any putative treatments that are developed are also likely to be given with concurrent antipsychotic treatment. While our knowledge of this devastating disorder increases and our animal models and tasks with which to measure their behaviors become more sophisticated, caution must still be taken when validating these models to limit complications when introducing putative therapeutics to human trials.