ANIMAL MODELS FOR STUDY OF NEUROTRANSMITTER FUNCTION/NEUROPHARMACOLOGIC EFFECTS

这个项目的主要目的是增加我们对5-羟色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另一个项目报告中描述的影响健康人类和强迫症和其他焦虑症患者的5-羟色胺能神经传递基因的类似研究平行进行。在过去的一年里，我们通过靶向干扰5-羟色胺(5-羟色胺)转运体来扩大小鼠的特征。这些小鼠(+/-鼠)减少了50%，完全缺乏转运蛋白(在-/-鼠)，在几种啮齿动物冲突行为模型中显示出自发的“焦虑增加”的行为表型，以及对应激条件更大的神经内分泌反应。在这些“敲除”的小鼠中，发现对两种滥用药物MDMA(3，4-亚甲二氧基苯丙胺，“摇头丸”)和可卡因以及对其他几种药物的反应与基因剂量有关。其他药物反应仅在-/-小鼠中发生改变；其中一些反映了预期的5-羟色胺-1A和其他5-羟色胺受体亚型的脱敏以及受体后信号机制的变化。

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.