Antipsychotic Drug Actions on Brain Neurochemistry

抗精神病药物对脑神经化学的作用

• 批准号: 6630138
• 负责人: Carol A Tamminga
• 金额: $ 33.46万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-29 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6630138
• 关键词: attention; autoradiography; behavior test; behavioral /social science research tag; bioassay; biological models; biomarker; central nervous system; cognition; disease /therapy duration; drug adverse effect; drug screening /evaluation; glutamate receptor; haloperidol; laboratory mouse; longitudinal animal study; mental disorder chemotherapy; neural inhibition; neurochemistry; neurotransmitters; pharmacokinetics; phencyclidine; psychomotor function; risperidone; schizophrenia; serotonin inhibitor; social adjustment

DESCRIPTION (provided by applicant): This grant application proposes laboratory research projects to continue a productive line of research into the behavioral, neurochemical, and anatomic characterization of new antipsychotic drugs. The new generation of antipsychotic drugs has swept clinical markets around the world because of the full clinical actions of the compounds and their reduced motor side effect profiles. This project aims to compare the two most widely used antipsychotics (risperidone and olanzapine), and contrast them with a traditional drug (haloperidol) in a chronic animal treatment model with informative mouse behavior, neurochemical and anatomic assays. We will test effects of the two new antipsychotic drugs and haloperidol on two mouse behaviors when applied acutely and after 1,2,3, and 4 months of antipsychotic treatment: (1) PCP-disrupted prepulse inhibition (PPI) (purportedly modeling for attentional dysfunction in schizophrenia) and (2) PCP-disruption of social learning (purportedly modeling for learning dysfunction). Concurrently, we will analyze neurochemical and anatomic markers of neurotransmitter pathways in CNS, especially in those regions where clinical schizophrenia studies have localized attentional and cognitive dysfunction. The behavioral, neurochemical, and anatomic changes will be correlated over treatment time in each drug group and contrasted between drugs. These studies are a continuation of a productive approach aimed at studying antipsychotic drug actions using behavior (oral dyskinesias) to mark the drug action and regional neurochemical correlates to establish the putative mechanism (see Progress Report). We can expect that new antipsychotic drugs will have not only actions on positive symptoms but also display low motor side effects (acute and chronic) and ameliorate the short term memory and the attentional dysfunction of schizophrenia. Animal measures of these "new" actions could expedite drug development in this "new" broader and more complex direction. Concentration on mouse behaviors, neurochemistry and behavior will advance studies aimed at kinetic applications.

描述（由申请人提供）：本拨款申请提出了实验室研究项目，以继续对新型抗精神病药物的行为、神经化学和解剖学特征进行富有成效的研究。新一代抗精神病药物因其化合物的全面临床作用及其减少的运动副作用而席卷了世界各地的临床市场。该项目旨在比较两种最广泛使用的抗精神病药物（利培酮和奥氮平），并在慢性动物治疗模型中与传统药物（氟哌啶醇）进行对比，并通过小鼠行为、神经化学和解剖学检测提供信息。我们将测试两种新的抗精神病药物和氟哌啶醇在急性应用以及抗精神病药物治疗 1、2、3 和 4 个月后对两种小鼠行为的影响：(1) PCP 破坏的前脉冲抑制 (PPI)（据称是注意力模型）精神分裂症的功能障碍）和（2）PCP-社交学习的破坏（据称是学习功能障碍的建模）。同时，我们将分析中枢神经系统神经递质通路的神经化学和解剖标志物，特别是在临床精神分裂症研究发现局部注意力和认知功能障碍的区域。每个药物组的行为、神经化学和解剖学变化将随着治疗时间的推移而相关，并在药物之间进行对比。这些研究是富有成效的方法的延续，旨在使用行为（口腔运动障碍）来研究抗精神病药物作用，以标记药物作用和区域神经化学相关性，以建立推定机制（参见进展报告）。我们可以预期，新的抗精神病药物不仅对阳性症状有效，而且还表现出低运动副作用（急性和慢性），并改善精神分裂症的短期记忆和注意力功能障碍。这些“新”作用的动物测量可以加速药物在这个“新”更广泛和更复杂的方向上的开发。对小鼠行为、神经化学和行为的关注将推进针对动力学应用的研究。