Peleg-Raibstein Daria, Feldon Joram, Meyer Urs
Swiss Federal Institute of Technology, Zürich, Switzerland.
Handb Exp Pharmacol. 2012(212):361-406. doi: 10.1007/978-3-642-25761-2_14.
Basic research in animals represents a fruitful approach to study the neurobiological basis of brain and behavioral disturbances relevant to neuropsychiatric disease and to establish and evaluate novel pharmacological therapies for their treatment. In the context of schizophrenia, there are models employing specific experimental manipulations developed according to specific pathophysiological or etiological hypotheses. The use of selective lesions in adult animals and the acute administration of psychotomimetic agents are indispensable tools in the elucidation of the contribution of specific brain regions or neurotransmitters to the genesis of a specific symptom or collection of symptoms and enjoy some degrees of predictive validity. However, they may be inaccurate, if not inadequate, in capturing the etiological mechanisms or ontology of the disease needed for a complete understanding of the disease and may be limited in the discovery of novel compounds for the treatment of negative and cognitive symptoms of schizophrenia. Under the prevailing consensus of schizophrenia as a disease of neurodevelopmental origin, we have seen the establishment of neurodevelopmental animal models which aim to identify the etiological processes whereby the brain, following specific triggering events, develops into a "schizophrenia-like brain" over time. Many neurodevelopmental models such as the neonatal ventral hippocampus (vHPC) lesion, methylazoxymethanol (MAM), and prenatal immune activation models can mimic a broad spectrum of behavioral, cognitive, and pharmacological abnormalities directly implicated in schizophrenic disease. These models allow pharmacological screens against multiple and coexisting schizophrenia-related dysfunctions while incorporating the disease-relevant concept of abnormal brain development. The multiplicity of existing models is testimonial to the multifactorial nature of schizophrenia, and there are ample opportunities for their integration. Indeed, one ultimate goal must be to incorporate the successes of distinct models into one unitary account of the complex disorder of schizophrenia and to use such unitary approaches in the further development and evaluation of novel antipsychotic treatment strategies.
动物基础研究是一种卓有成效的方法，可用于研究与神经精神疾病相关的脑和行为障碍的神经生物学基础，并建立和评估用于治疗这些疾病的新型药物疗法。在精神分裂症的背景下，有一些模型采用了根据特定病理生理或病因假说开发的特定实验操作。在成年动物中使用选择性损伤以及急性给予拟精神病药物，是阐明特定脑区或神经递质对特定症状或症状群发生发展的贡献的不可或缺的工具，并且具有一定程度的预测效度。然而，它们在捕捉疾病的病因机制或本体论（这对于全面理解疾病是必需的）方面可能不准确，甚至不充分，并且在发现用于治疗精神分裂症阴性和认知症状的新型化合物方面可能存在局限性。在精神分裂症是神经发育起源疾病这一普遍共识下，我们看到了神经发育动物模型的建立，其目的是确定病因过程，即大脑在特定触发事件后，随着时间的推移发展成为“精神分裂症样大脑”。许多神经发育模型，如新生儿腹侧海马体（vHPC）损伤模型、甲基偶氮甲醇（MAM）模型和产前免疫激活模型，可以模拟一系列直接与精神分裂症相关的行为、认知和药理学异常。这些模型允许针对多种并存的与精神分裂症相关的功能障碍进行药理学筛选，同时纳入与疾病相关的异常脑发育概念。现有模型的多样性证明了精神分裂症的多因素性质，并且有充分的机会将它们整合起来。事实上，一个最终目标必须是将不同模型的成功之处整合到对精神分裂症这种复杂疾病的统一解释中，并在新型抗精神病治疗策略的进一步开发和评估中使用这种统一方法。
