Clozapine Drug Discrimination in C57BL/6J Mice

描述（由申请人提供）：氯氮平是典型的非典型抗精神病药物，在治疗精神分裂症的疗效和降低副作用倾向方面，与传统抗精神病药物相比有了巨大的改进。了解氯氮平独特的药理学特性有助于发现更好、更安全的抗精神病药物来治疗精神分裂症。一种研究药理学试剂和行为之间关系的分子基础的方法是使用基因靶向敲除或转基因动物。该技术允许操纵不存在选择性药理学配体的受体。这种方法的一个限制是，大多数已经开发的敲除突变只能在小鼠中获得，而不能在大鼠中获得。因此，有必要对小鼠进行临床前试验，以利用这些新的和潜在的强大的新技术。 目前的建议是这一进程中重要的第一步。双杠杆药物辨别是一种有价值的临床前行为模型，已被用于研究大鼠中氯氮平的辨别性刺激特性，并有助于确定推定的非典型抗精神病药的神经递质受体靶点。将训练野生型小鼠（C57 BL/6 J）区分氯氮平与媒介物，然后测试一系列非典型和典型抗精神病药物以确定哪些药物概括为氯氮平的区分线索。在野生型小鼠中建立这一程序将允许将来使用基因敲除和转基因小鼠，并将扩展分子遗传学家和行为药理学家可用的工具。这将有助于增加我们对精神分裂症令人困惑的药理学的理解。

DESCRIPTION (provided by applicant): Clozapine is the prototypical atypical antipsychotic drug and represents a tremendous improvement over conventional antipsychotics in terms of therapeutic efficacy and reduced side effect liability for the treatment of schizophrenia. Understanding the pharmacological properties that are important for clozapine's unique profile can help lead to the discovery of improved and safer antipsychotic drugs for the treatment of schizophrenia. One approach for investigating the molecular bases underlying the relationship of pharmacological agents and behavior has been the use of gene-targeted knockout or transgenic animals. This technique allows for the manipulation of receptors for which selective pharmacological ligands do not exist. One restriction of this approach is that most of the knockout mutations that have been developed are available only in mice - not rats. Therefore, it is necessary to have preclinical assays for mice in order to utilize these new and potentially powerful new techniques. The current proposal represents an important first step in this process. Two-lever drug discrimination is a valuable preclinical behavioral model that has been used to investigate the discriminative stimulus properties of clozapine in rats and has helped identify neurotransmitter receptor targets for putative atypical antipsychotics. Wild-type mice (C57BL/6J) will be trained to discriminate clozapine from vehicle and then a series of atypical and typical antipsychotic drugs will be tested to determine which drugs generalize to clozapine's discriminative cue. Establishing this procedure in wild-type mice will allow for the future use of knockout and transgenic mice and will expand the tools available to molecular geneticists and behavioral pharmacologists. This will help to increase our understanding of the perplexing pharmacology of schizophrenia.