SEROTONIN RELEASE AND BEHAVIOR

行为学和电生理学研究表明，对大脑的调节 5-羟色胺(5-羟色胺)的释放可能参与了新的临床效应。 精神治疗药物，特别是5-羟色胺摄取抑制剂，如 氟西汀是抗抑郁药和5-羟色胺(1A)受体激动剂，如 丁螺环酮是抗焦虑和抗抑郁药。有证据表明 长期服用SSRIs会产生脱敏作用 突触前5-羟色胺(1A)受体可能至少部分解释了 从药物治疗开始到出现的滞后时间 治疗效果。此外，临床研究表明， 联合应用5-羟色胺(1A)自身受体拮抗剂可增强 SSRIs的临床效果。体内微透析新技术 允许在不同的脑区测量5-羟色胺的释放 叫醒不受约束的动物。这项技术非常适合于直接 研究心理治疗药物对心理障碍的调节能力 突触前5-羟色胺(1A)受体调节5-羟色胺释放并测定 5-羟色胺释放的改变是否参与了他们的行为影响。 该项目的第一个目标将是为 SSRIs和MAOIs对脑内5-羟色胺释放的调节作用 改变突触前5-羟色胺功能的纹状体和海马区(1A) 自体感受器。其他研究将检查时间进程 停药后5-羟色胺(1A)受体敏感性的恢复 药物治疗。放射性配基结合研究将检查细胞内 中缝G蛋白偶联的5-羟色胺(1A)受体密度 使用本计划开发的新的选择性配体。其他研究 将检查慢性给药8-OH-DPAT的能力 修饰5-羟色胺(1A)自身受体调节5-羟色胺释放的功能 在纹状体和海马区，2)评估能力的变化 SSRIs可使细胞外5-羟色胺在治疗前升高。 最后，选择性拮抗剂的联合给药能力 5-羟色胺(1A)和5-羟色胺(1B)受体对SSRIs的影响 慢性给药后细胞外5-羟色胺浓度 将对SSRIs进行研究。 拟议工作的结果应对以下方面产生重要影响 我们对大脑中突触传递及其影响的理解 精神治疗药物。

Behavioral and electrophysiologic studies suggest that the regulation of serotonin (5-HT) release may be involved in the clinical effects of new psychotherapeutic drugs, particularly 5-HT uptake inhibitors such as fluoxetine that are antidepressants and 5-HT(1A) receptor agonists such as buspirone that are anxiolytics and antidepressants. Evidence suggests that chronic administration of SSRIs produces desensitization of presynaptic 5-HT(1A) receptors that may account for, at least in part, the lag time between the initiation of drug treatment and the appearance of therapeutic effects. In addition, clinical studies suggest that coadministration of antagonists of 5-HT(1A) autoreceptors can potentiate the clinical effects of SSRIs. The new technique of in vivo microdialysis permits the release of 5-HT to be measured in discrete brain regions in awake unrestrained animals. This technique is ideally suited to directly study the ability of psychotherapeutic drugs to regulate the ability of presynaptic 5-HT(1A) receptors to modify 5-HT release and to determine whether altered 5-HT release is involved in their behavioral effects. The first goal of this project will be to establish the time course for the ability of SSRIs and MAOIs to regulate the release of 5-HT in the striatum and hippocampus by modifying the function of presynaptic 5-HT(1A) autoreceptors. Additional studies will examine the time course of recovery of 5-HT(1A) receptor sensitivity after the discontinuation of drug treatment. Radioligand binding studies will examine changes in the density of 5-HT(1A) receptors in the raphe that are coupled to G proteins using new selective ligands developed by this Program. Additional studies will examine the ability of chronic administration of 8-OH-DPAT to 1) modify the function of 5-HT(1A) autoreceptors that regulate 5-HT release in the striatum and hippocampus and 2) to evaluate changes in the ability of SSRIs to increase extracellular 5-HT after prior treatment. Finally, the ability of coadministration of antagonists that are selective for 5-HT(1A) and 5-HT(1B) receptors to modify the effects of SSRIs on extracellular concentrations of 5-HT after and chronic administration of SSRIs will be studied. The results of the proposed work should have important implications for our understanding of synaptic transmission in the brain and of the effects of psychotherapeutic drugs.