ANIMAL MODELS FOR STUDY OF NEUROTRANSMITTER FUNCTION/NEUROPHARMACOLOGIC EFFECTS

这个项目的主要目的是增加我们对血清素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在其他项目报告中描述的影响健康人、强迫症患者和其他焦虑症患者血清素能神经传递的类似基因研究同时进行。在过去的一年里，我们扩展了小鼠的特征，有针对性地破坏血清素（5-HT）转运体。这些小鼠的转运体减少了50%（在+/-小鼠中），完全缺乏（在-/-小鼠中），在几种啮齿动物冲突行为模型中表现出自发性的“增加焦虑”行为表型，以及对压力条件的更大的神经内分泌反应。研究发现，在这些被“敲除”的小鼠中，对滥用MDMA（3,4-亚甲基二氧基安非他明，“摇头丸”）和可卡因这两种药物的反应，以及对其他几种药物的反应，都发生了基因剂量依赖性的改变。其他药物反应仅在-/-小鼠中发生改变；其中一些反映了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.