ALTERED SEROTONIN SIGNAL TRANSDUCTION IN DYSKINESIAS

运动障碍中血清素信号转导的改变

• 批准号: 2501490
• 负责人: WILLIAM A. WOLF
• 金额: $ 15.76万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-03-01 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2501490
• 关键词: G protein; abnormal involuntary movement; basal ganglia; behavioral /social science research tag; drug adverse effect; drug interactions; enzyme activity; haloperidol; ketanserin; laboratory rat; neural transmission; neuropharmacology; phospholipase C; receptor expression; serotonin; serotonin receptor

The long term objective of this research is to determine the neurochemical mechanisms underlying antipsychotic-induced dyskinesias. Antipsychotics, such as haloperidol, are widely used in the treatment of schizophrenia and in agitated elderly patients. However, a substantial proportion of patients receiving antipsychotic medication experience motor disorders, often referred to as extrapyramidal side effects (EPS). In fact, the incidence of EPS can approach 100 percent in the elderly. Currently, no antipsychotics exist which are both safe to use and free of EPS liability. It is hoped that by understanding how these drugs affect neuronal systems involved in motor control, safer compounds with no motoric side effects can be developed. One neurotransmitter involved in motor control and implicated in mediating EPS, is serotonin (5-hydroxytryptamine; 5-HT). Drugs which increase central serotonergic activity can elicit orofacial dyskinesias in both non-human primates and rats which have received antipsychotic treatment, but not in vehicle-pretreated animals. Similar orofacial dyskinesias are often seen in patients on antipsychotic medication. While experimental data suggests that the serotonin 5-HT2c receptor mediates orofacial dyskinesias, the effects of antipsychotics on 5-HT2c mediated motor control and 5-HT2c-linked signal transduction in the brain have not been studied. In this proposal it is hypothesized that 5-HT2c receptor supersensitivity in the basal ganglia contributes to the EPS caused by antipsychotic drugs. The first specific aim is to determine that 21 day administration of haloperidol to rats increases 5-HT2c mediated motor activity in vivo. This will be accomplished by comparing 5-HT2c-mediated orofacial dyskinesias between haloperidol- treated and vehicle-treated rats. The effects of haloperidol on 5-HT2c receptor-mediated signal transduction in basal ganglia will also be assessed in Aim I. For this purpose, 5-HT2c-stimulated phospholipase C activity in caudate and substantia nigra of haloperidol-treated and vehicle treated rats will be assayed. To determine the receptor transduction mechanism through which supersensitivity occurs, radioligand binding assays will assess changes in the 5-HT2c ligand recognition site and immunoblotting techniques will assess changes in guanine-nucleotide binding regulatory proteins which couple the 5-HT2c site to phospholipase C. The second specific aim is to attenuate the induction of dyskinesias and receptor supersensitivity by chronically co-administering agents known to down-regulate the 5-HT2c receptor. The success of this approach will be determined biochemically and behaviorally as Aim I.

这项研究的长期目标是确定 抗精神病药引起的运动障碍的神经化学机制。 抗精神病药，例如氟哌啶醇，被广泛用于治疗 精神分裂症和躁动的老年患者。 但是， 接受抗精神病药物的患者中很大一部分 体验运动障碍，通常称为锥体外侧 效果（EPS）。 实际上，每股收益的发生率可以接近100％ 在老人。目前，不存在任何抗精神病药 使用并不受EPS责任。 希望通过理解 这些药物如何影响与运动控制有关的神经元系统， 可以开发出没有摩尔副作用的更安全的化合物。一 与运动控制有关的神经递质与介导有关 EPS是5-羟色胺（5-羟色胺； 5-HT）。 增加的药物 中央血清素能活性都可以引起两者的口面性运动障碍 接受抗精神病药的非人类灵长类动物和大鼠 治疗，但不在媒介物预处理的动物中。 类似的口面 抗精神病药物患者经常会看到运动障碍。 虽然实验数据表明5-羟色胺5-HT2C受体 介导口质运动障碍，抗精神病药对5-HT2C的影响 介导的运动控制和5-HT2C连接的信号转导 尚未研究大脑。 在此提案中，假设 基底神经节中的5-HT2C受体超敏反应有助于 由抗精神病药引起的EPS。 第一个具体目的是 确定21天给大鼠氟哌啶醇的给药增加 5-HT2C体内介导的运动活性。 这将通过 比较氟哌啶醇之间的5-HT2C介导的口面性运动障碍 经过治疗和车辆处理的大鼠。 氟哌啶醇对5-HT2C的影响 受体介导的基础神经节中的信号转导也将是 在AIM I中进行评估。为此，5-HT2C刺激的磷脂酶 C活性在氟哌啶醇治疗的尾状和黑质中 将分析经车辆治疗的大鼠。 确定受体 超敏反应的转导机制， 放射性结合测定将评估5-HT2C配体的变化 识别地点和免疫印迹技术将评估变化 鸟嘌呤核苷酸结合调节蛋白，将5-HT2C融合 磷脂酶C. 长期诱导运动障碍和受体超敏反应 已知可下调5-HT2C受体的共同给药剂。 这种方法的成功将以生化确定，并 作为目标。