MAPPING THE GENES FOR NEUROLEPTIC RESPONSE

绘制神经抑制反应的基因图谱

• 批准号: 2250625
• 负责人: ROBERT J. HITZEMANN
• 金额: $ 11.68万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-12-01 至 1997-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2250625
• 关键词: animal genetic material tag; antipsychotic agents; autoradiography; behavioral genetics; catalepsy; dopamine receptor; extrapyramidal disorder; gene frequency; genetic mapping; genetic markers; genetic polymorphism; genetic strain; genotype; haloperidol; laboratory mouse; pharmacokinetics; phenotype; polymerase chain reaction; receptor binding; receptor sensitivity; restriction fragment length polymorphism; statistics /biometry

In general, new strategies to reduce neuroleptic-induced extrapyramidal symptoms (EPS) focus on understanding the mechanisms of action of the atypical antipsychotic drugs (e.g. clozapine). The proposed research adopts a different strategy and attempts to understand from the genetic perspective the wide natural variation in drug response. We use neuroleptic-induced catalepsy in the mouse as a model to investigate the mechanisms responsible for the variability in EPS. Our working hypothesis is that the variability in this behavior is at least in part inherited. In addition, we propose that this complex behavior is under the control of multiple genes, rather than one or two major genes. The BXD/Ty recombinant inbred (RI) strains are used as a tool in detecting and mapping the locations of the relevant genes. The chromosomal position of these genes can be estimated by quantitative trait loci (QTL) analysis which seeks to discover significant associations between the phenotype of interest and multiple gene markers which have been previously mapped. For statistical reasons, this analysis is best viewed as an exploratory tool for identifying candidate QTL, which need independent confirmation. B6D2 F2 mice, typed for haloperidol sensitivity, will be used to confirm the candidate QTL. This confirmatory analysis will emphasize PCR based microsatellite genotyping. In preliminary results, one QTL detected by this 'two-step' approach is either near or part of the D2 dopamine receptor gene (Drd2). The question arises as to whether or not the QTL detected by the RI/F2 approach can be extended to the general population. To address this question, it is proposed to screen the confirmed QTL in the neuroleptic responsive (NR/Np) and neuroleptic non-responsive (NNR/Np) selected lines which were derived from a recently created heterogenous stock (HS/Np). Alleles conferring response should be over-represented in the NR/Np line, while those conferring non-response should predominate in the NNR/Np line. Animals from S2, S4 and S8 will be genotyped; these generations cover the period of the most marked segregation of the relevant alleles. In the BXD/Ty series, QTL which account for < 16% of the variance will not be detected. Methods to detect smaller but measurable QTL have been suggested e.g. the use of F1 crosses between RI strains as a means of increasing power. An alternative approach for detecting these smaller QTL is proposed which makes use of the knowledge that haloperidol-induced catalepsy results from blockade of D2 dopamine receptors. Furthermore, it has been demonstrated that the variation in haloperidol response among selected lines, inbred strains and B6D2 F2 hybrids is strongly associated with somatodendritic D2 receptor density. It is proposed to map and confirm, using the RI/F2 approach, QTL for somatodendritic D2 receptor density. The confirmed QTL will then be screened in a large population (N = 150) of F2 hybrids phenotyped for haloperidol response. If successful, this approach will not only detect additional QTL for haloperidol response but for some QTL will also assign functional attributes.

通常，减少神经肌动蛋白诱导的腹膜外的新策略 症状（EP）专注于理解行动机制 非典型抗精神病药（例如氯氮平）。拟议的研究 采取不同的策略，并试图从遗传中理解 透视药物反应的广泛自然变化。我们使用 在小鼠中神经肌肉诱导的催化症作为研究的模型 负责EPS变异性的机制。我们的工作假设 是至少部分继承了这种行为的变异性。在 此外，我们建议这种复杂的行为在 多个基因，而不是一个或两个主要基因。 BXD/TY重组 近交（RI）菌株被用作检测和映射的工具 相关基因的位置。这些基因的染色体位置 可以通过定量性状基因座（QTL）分析来估计，该分析试图 发现感兴趣的表型与 以前已映射的多个基因标记。用于统计 原因，最好将此分析视为探索性工具 识别需要独立确认的候选QTL。 B6D2 F2 用于氟哌啶醇敏感性的小鼠将用于确认 候选QTL。这种确认性分析将强调基于PCR的 微卫星基因分型。在初步结果中，一个QTL检测到 这种“两步”方法接近D2多巴胺或一部分 受体基因（DRD2）。 关于RI/F2检测到的QTL是否出现了问题 方法可以扩展到一般人群。解决这个问题 问题，提议筛选神经疗法中确认的QTL 响应式（NR/NP）和神经肌激素非反应性（NNR/NP）选定的线 源自最近创建的异质股（HS/NP）。 等位基因赋予响应的等位基因应在NR/NP线中过分代表， 而那些赋予无响应的人应在NNR/NP线中占主导地位。 S2，S4和S8的动物将被基因分型；这些几代人涵盖了 相关等位基因最明显的隔离期。 在BXD/TY系列中，占差异<16％的QTL不会 被检测到。检测较小但可测量的QTL的方法已经 建议在RI菌株之间使用F1交叉作为 力量增加。检测这些较小QTL的另一种方法 提出了利用氟哌啶醇引起的知识 僵化导致D2多巴胺受体的封锁。此外，它 已证明氟哌啶醇反应之间的变化 选定的线，近交菌株和B6D2 F2杂种密切相关 与体体D2受体密度。建议映射 确认使用RI/F2方法，QTL用于somatendritic D2受体 密度。然后，确认的QTL将在大量人群中进行筛选（n = 150）的F2杂种，用于氟哌啶醇反应。如果成功， 这种方法不仅可以检测到氟哌啶醇响应的其他QTL 但是对于某些QTL也将分配功能属性。