Boehmler W, Carr T, Thisse C, Thisse B, Canfield V A, Levenson R
Department of Pharmacology, Penn State College of Medicine, Hershey, PA 17033, USA.
Genes Brain Behav. 2007 Mar;6(2):155-66. doi: 10.1111/j.1601-183X.2006.00243.x.
Zebrafish, a model developmental genetic organism, is being increasingly used in behavioural studies. We have initiated studies designed to evaluate the response of zebrafish to antipsychotic drugs. This study focuses on characterization of zebrafish D4 dopamine receptors (D4Rs) and the response of larval zebrafish to the atypical antipsychotic clozapine. The D4R is of interest because of its high affinity for clozapine, while interest in clozapine stems from its effectiveness in reducing symptoms in acutely psychotic, treatment-resistant schizophrenic patients. By mining the zebrafish genomic database, we identified three distinct D4R genes, drd4a, drd4b and drd4c, and generated full-length open reading frames encoding each of the three D4Rs by reverse transcription-polymerase chain reaction. Gene mapping studies showed that each D4R gene mapped to a distinct chromosomal location in the zebrafish genome, and each gene exhibited a unique expression profile during embryogenesis. When administered to larval zebrafish, clozapine produced a rapid and profound effect on locomotor activity. The effect of clozapine was dose-dependent, resulted in hypoactivity and was prevented by the D4-selective agonist ABT-724. Our data suggest that the inhibitory effect of clozapine on the locomotor activity of larval zebrafish may be mediated through D4Rs.
斑马鱼是一种模式发育遗传生物，越来越多地用于行为研究。我们已启动旨在评估斑马鱼对抗精神病药物反应的研究。本研究重点是斑马鱼D4多巴胺受体（D4Rs）的特性以及斑马鱼幼体对非典型抗精神病药物氯氮平的反应。D4R因其对氯氮平具有高亲和力而受到关注，而对氯氮平的关注源于其在减轻急性精神病性、难治性精神分裂症患者症状方面的有效性。通过挖掘斑马鱼基因组数据库，我们鉴定出三个不同的D4R基因，即drd4a、drd4b和drd4c，并通过逆转录-聚合酶链反应生成了编码这三种D4R的全长开放阅读框。基因定位研究表明，每个D4R基因都定位于斑马鱼基因组中一个不同的染色体位置，并且每个基因在胚胎发育过程中都表现出独特的表达谱。当给斑马鱼幼体施用氯氮平时，它对运动活性产生了快速而显著的影响。氯氮平的作用是剂量依赖性的，导致活动减少，并且可被D4选择性激动剂ABT-724阻断。我们的数据表明，氯氮平对斑马鱼幼体运动活性的抑制作用可能是通过D4Rs介导的。
