ANIMAL MODELS FOR STUDY OF NEUROTRANSMITTER FUNCTION/NEUROPHARMACOLOGIC EFFECTS

这个项目的主要目的是增加我们对多巴胺能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我们其他项目报告中描述的影响健康人和强迫症及其他焦虑症患者中多巴胺能神经传递的基因的类似研究平行进行。在过去的一年中，我们已经扩展了小鼠的特性与5-羟色胺（5-HT）转运蛋白的靶向中断。这些小鼠的转运蛋白减少了50%（+/-小鼠）和完全缺乏（-/-小鼠），在几种啮齿动物冲突行为模型中表现出增加的“焦虑”的自发行为表型，以及对应激条件的更大神经内分泌反应。 在这些基因敲除小鼠中，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反应是基因剂量依赖性的。其他药物反应仅在-/-小鼠中改变;其中一些反应反映了5-HT-1A和其他5-羟色胺受体亚型的预期脱敏以及受体后信号传导机制的变化。

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.