Departamento de Farmacologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
Programa de Pós-graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
Curr Neuropharmacol. 2022 Mar 4;20(3):494-509. doi: 10.2174/1570159X19666210215121428.
Schizophrenia pathophysiology is associated with hypofunction of glutamate NMDA receptors (NMDAR) in GABAergic interneurons and dopaminergic hyperactivation in subcortical brain areas. The administration of NMDAR antagonists is used as an animal model that replicates behavioral phenotypes relevant to the positive, negative, and cognitive symptoms of schizophrenia. Such models overwhelmingly rely on rodents, which may lead to species-specific biases and poor translatability. Zebrafish, however, is increasingly used as a model organism to study evolutionarily conserved aspects of behavior. We thus aimed to review and integrate the major findings reported in the zebrafish literature regarding the behavioral effects of NMDAR antagonists with relevance to schizophrenia. We identified 44 research articles that met our inclusion criteria from 590 studies retrieved from MEDLINE (PubMed) and Web of Science databases. Dizocilpine (MK-801) and ketamine were employed in 29 and 10 studies, respectively. The use of other NMDAR antagonists, such as phencyclidine (PCP), APV, memantine, and tiletamine, was described in 6 studies. Frequently reported findings are the social interaction and memory deficits induced by MK-801 and circling behavior induced by ketamine. However, mixed results were described for several locomotor and exploratory parameters in the novel tank and open tank tests. The present review integrates the most relevant results while discussing variation in experimental design and methodological procedures. We conclude that zebrafish is a suitable model organism to study drug-induced behavioral phenotypes relevant to schizophrenia. However, more studies are necessary to further characterize the major differences in behavior as compared to mammals.
精神分裂症的病理生理学与 GABA 能中间神经元谷氨酸 NMDA 受体 (NMDAR) 的功能低下和皮质下脑区多巴胺能的过度激活有关。NMDAR 拮抗剂的给药被用作一种动物模型，可复制与精神分裂症的阳性、阴性和认知症状相关的行为表型。此类模型主要依赖于啮齿动物，这可能导致种间特异性偏见和较差的可翻译性。然而，斑马鱼越来越多地被用作研究行为中进化保守方面的模型生物。因此，我们旨在综述和整合斑马鱼文献中关于 NMDAR 拮抗剂对精神分裂症相关行为影响的主要发现。我们从 MEDLINE（PubMed）和 Web of Science 数据库中检索到的 590 项研究中，确定了符合纳入标准的 44 篇研究文章。地卓西平（MK-801）和氯胺酮分别在 29 项和 10 项研究中使用。在 6 项研究中描述了其他 NMDAR 拮抗剂，如苯环己哌啶 (PCP)、APV、美金刚和替来他明的使用。经常报道的发现是 MK-801 诱导的社交互动和记忆缺陷以及氯胺酮诱导的转圈行为。然而，在新奇坦克和开放坦克测试中，几个运动和探索参数的描述结果是混合的。本综述在讨论实验设计和方法学程序的差异的同时，整合了最相关的结果。我们得出的结论是，斑马鱼是研究与精神分裂症相关的药物诱导行为表型的合适模型生物。然而，还需要更多的研究来进一步描述与哺乳动物相比行为的主要差异。
