Laboratório de Neuroquímica e Psicofarmacologia, Departamento de Biologia Celular e Molecular, Programa de Pós-Graduação em Biologia Celular e Molecular. Faculdade de Biociências, Pontifícia Universidade Católica do Rio Grande do Sul, Avenida Ipiranga, 6681, 90619-900, Porto Alegre, RS, Brazil.
Behav Brain Res. 2011 Oct 10;224(1):135-9. doi: 10.1016/j.bbr.2011.05.034. Epub 2011 Jun 6.
Schizophrenia is a severe mental illness characterized by positive and negative symptoms and cognitive deficits. Reduction of glutamatergic neurotransmission by NMDA receptor antagonists mimics symptoms of schizophrenia. Modeling social interaction and cognitive impairment in animals can be of great benefit in the effort to develop novel treatments for negative and cognitive symptoms of schizophrenia. Studies have demonstrated that these behavioral changes are, in some cases, sensitive to remediation by antipsychotic drugs. The zebrafish has been proposed as a candidate to study the in vivo effects of several drugs and to discover new pharmacological targets. In the current study we investigated the ability of antipsychotic drugs to reverse schizophrenia-like symptoms produced by the NMDA receptor antagonist MK-801. Results showed that MK-801 (5μM) given pre-training hindered memory formation while both atypical antipsychotics sulpiride (250μM) and olanzapine (50μM) improved MK-801-induced amnesia. The same change was observed in the social interaction task, where atypical antipsychotics reversed the MK-801-induced social interaction deficit whereas the typical antipsychotic haloperidol (9μM) was ineffective to reverse those behavioral deficits. Therefore, MK-801-treated zebrafish showed some behavioral features observed in schizophrenia, such as cognitive and social interaction deficits, which were reverted by current available atypical drugs.
精神分裂症是一种严重的精神疾病，其特征为阳性症状、阴性症状和认知缺陷。NMDA 受体拮抗剂减少谷氨酸能神经传递可模拟精神分裂症的症状。在动物中模拟社会互动和认知障碍对于开发新型精神分裂症阴性和认知症状的治疗方法具有重要意义。研究表明，这些行为变化在某些情况下对抗精神病药物的治疗具有敏感性。斑马鱼已被提议用于研究几种药物的体内作用并发现新的药理学靶点。在本研究中，我们研究了抗精神病药物是否能够逆转 NMDA 受体拮抗剂 MK-801 产生的类精神分裂症症状。结果表明，MK-801（5μM）在训练前给药会阻碍记忆形成，而两种非典型抗精神病药舒必利（250μM）和奥氮平（50μM）则改善了 MK-801 引起的健忘症。在社会互动任务中也观察到了相同的变化，非典型抗精神病药逆转了 MK-801 引起的社交互动缺陷，而典型抗精神病药氟哌啶醇（9μM）则无效。因此，MK-801 处理的斑马鱼表现出一些在精神分裂症中观察到的行为特征，如认知和社会互动缺陷，这些缺陷可以被现有可用的非典型药物逆转。
