ANIMAL MODELS FOR STUDY OF NEUROTRANSMITTER FUNCTION/NEUROPHARMACOLOGIC EFFECTS

用于研究神经递质功能/神经药理学作用的动物模型

• 批准号: 6432770
• 负责人: DENNIS L MURPHY
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6432770
• 关键词: NMDA receptors; disease /disorder model; gene targeting; genetically modified animals; laboratory mouse; neuropharmacology; psychopharmacology; receptor sensitivity; serotonin; serotonin receptor; serotonin transporter; superoxide dismutase

The primary aim of this project is to increase our understanding of the role of the serotonergic neurotransmitter system in behavior. Animal model studies described in this project are done in parallel with analogous studies of genes affecting serotonergic neurotransmission in healthy humans and in patients with obsessive-compulsive disorder and other anxiety disorders as described in our other project report. In the last year, we have extended the characterization of mice with a targeted disruption of the serotonin (5-HT) transporter. These mice, which have a 50% reduction (in +/- mice) and a complete lack (in -/- mice) of the transporter, demonstrate a spontaneous behavioral phenotype of increased "anxiety in several models of rodent conflict behavior as well as greater neuroendocrine responses to stressful conditions. Responses to two drugs of abuse, MDMA (3,4-methylenedioxymeth-amphetamine, "ecstasy") and cocaine, and to several other drugs were found to be gene-dose-dependently altered in these "knock-out" mice. Other drug responses were only altered in -/- mice; some of these reflected expected desensitization of 5-HT-1A, and other serotonin receptor subtypes as well as changes in post-receptor signaling mechanisms.

该项目的主要目的是加深我们对血清素神经递质系统在行为中的作用的理解。 本项目中描述的动物模型研究与影响健康人类和强迫症和其他焦虑症患者血清素神经传递的基因的类似研究同时进行，如我们其他项目报告中所述。去年，我们通过有针对性地破坏血清素 (5-HT) 转运蛋白来扩展小鼠的特征。这些小鼠的转运蛋白减少了 50%（+/- 小鼠），并且完全缺乏（-/- 小鼠），在几种啮齿动物冲突行为模型中表现出“焦虑”增加的自发行为表型以及研究发现，对两种滥用药物 MDMA（3,4-亚甲二氧基甲基苯丙胺，“摇头丸”）和可卡因以及其他几种药物的神经内分泌反应更强。这些“基因敲除”小鼠中的其他药物反应仅发生基因剂量依赖性改变；其中一些反映了 5-HT-1A 和其他血清素受体亚型的预期脱敏以及受体后信号传导机制。