SEROTONIN RELEASE AND BEHAVIOR

行为和电生理学研究表明， 5-羟色胺（5-HT）的释放可能参与了新的 精神治疗药物，特别是5-HT摄取抑制剂， 氟西汀是抗抑郁药和5-HT（1A）受体激动剂， 丁螺环酮是抗焦虑和抗抑郁药。 证据表明 长期服用SSRIs会导致 突触前5-HT（1A）受体，可能至少部分解释了 药物治疗开始与出现 治疗效果 此外，临床研究表明， 5-HT（1A）自身受体拮抗剂的联合给药可增强 SSRIs的临床效果 活体微透析新技术 允许5-HT的释放被测量在离散的脑区域中， 唤醒不受约束的动物 这种技术非常适合直接 研究精神治疗药物调节神经功能的能力， 突触前5-HT（1A）受体调节5-HT释放，并确定 5-HT释放的改变是否与其行为效应有关。 本项目的第一个目标是确定 SSRIs和MAOIs调节5-HT释放的能力， 纹状体和海马突触前5-HT（1A）的功能 自体感受器 更多的研究将研究 停药后5-HT（1A）受体敏感性的恢复 药物治疗 放射性配体结合研究将检查 与G蛋白偶联的中缝中5-HT（1A）受体的密度 使用本计划开发的新的选择性配体。 其他研究 将检查长期施用8-OH-DPAT的能力，以1） 改变调节5-HT释放的5-HT（1A）自身受体的功能 在纹状体和海马体和2）评估能力的变化， SSRIs增加细胞外5-HT。 最后，选择性拮抗剂的联合给药能力 5-HT（1A）和5-HT（1B）受体的作用，以改变SSRIs对 5-HT的细胞外浓度后和慢性给药 将研究SSRI。 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.