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减少副作用方面比传统抗精神病药物有了巨大的改进。了解氯氮平独特的药理特性有助于发现更安全的抗精神病药物来治疗精神分裂症。研究药理学药物和行为之间关系的分子基础的一种方法是使用基因靶向敲除或转基因动物。这种技术允许对不存在选择性药理学配体的受体进行操纵。这种方法的一个限制是，大多数已经开发的基因敲除突变只适用于小鼠，而不是大鼠。因此，为了利用这些新的和潜在的强大的新技术，有必要对小鼠进行临床前检测。

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.