Castagné Vincent, Moser Paul C, Porsolt Roger D
Porsolt & Partners Pharmacology, 9 Bis Rue Henri Martin, 92100 Boulogne-Billancourt, France.
Adv Pharmacol. 2009;57:381-418. doi: 10.1016/S1054-3589(08)57010-4. Epub 2009 Nov 27.
Schizophrenia is a major psychiatric disease that is characterized by three distinct symptom domains: positive symptoms, negative symptoms, and cognitive impairment. Additionally, treatment with classical antipsychotic medication can be accompanied by important side effects that involve extrapyramidal symptoms (EPS). The discovery of clozapine in the 1970s, which is efficacious in all three symptom domains and has a reduced propensity to induce EPS, has driven research for new antipsychotic agents with a wider spectrum of activity and a lower propensity to induce EPS. The following chapter reviews existing behavioral procedures in animals for their ability to predict compound efficacy against schizophrenia symptoms and liability to induce EPS. Rodent models of positive symptoms include procedures related to hyperfunction in central dopamine and serotonin (5-hydroxytryptamine) systems and hypofunction of central glutamatergic (N-methyl-d-aspartate) neurotransmission. Procedures for evaluating negative symptoms include rodent models of anhedonia, affective flattening, and diminished social interaction. Cognitive deficits can be assessed in rodent models of attention (prepulse inhibition (PPI), latent inhibition) and of learning and memory (passive avoidance, object and social recognition, Morris water maze, and operant-delayed alternation). The relevance of the conditioned avoidance response (CAR) is also discussed. A final section reviews animal procedures for assessing EPS liability, in particular parkinsonism (catalepsy), acute dystonia (purposeless chewing in rodents, dystonia in monkeys), akathisia (defecation in rodents), and tardive dyskinesia (long-term antipsychotic treatment in rodents and monkeys).
精神分裂症是一种主要的精神疾病，其特征在于三个不同的症状领域：阳性症状、阴性症状和认知障碍。此外，使用经典抗精神病药物治疗可能会伴有涉及锥体外系症状（EPS）的重要副作用。20世纪70年代氯氮平的发现，它对所有三个症状领域都有效，并且诱发EPS的倾向较低，推动了对具有更广泛活性谱和更低诱发EPS倾向的新型抗精神病药物的研究。以下章节回顾了动物中现有的行为程序，以评估其预测化合物对精神分裂症症状疗效以及诱发EPS可能性的能力。阳性症状的啮齿动物模型包括与中枢多巴胺和5-羟色胺系统功能亢进以及中枢谷氨酸能（N-甲基-D-天冬氨酸）神经传递功能减退相关的程序。评估阴性症状的程序包括快感缺失、情感平淡和社交互动减少的啮齿动物模型。认知缺陷可在注意力（前脉冲抑制（PPI）、潜伏抑制）以及学习和记忆（被动回避、物体和社交识别、莫里斯水迷宫和操作性延迟交替）的啮齿动物模型中进行评估。还讨论了条件性回避反应（CAR）的相关性。最后一部分回顾了评估EPS可能性的动物程序，特别是帕金森症（僵住症）、急性肌张力障碍（啮齿动物无目的咀嚼、猴子肌张力障碍）、静坐不能（啮齿动物排便）和迟发性运动障碍（啮齿动物和猴子的长期抗精神病治疗）。
