PREPUBESCENT SSRIS & 5HT RECEPTOR SIGNALLING

青春期前SSRIS

• 批准号: 6477105
• 负责人: GEORGE BATTAGLIA
• 金额: $ 26.75万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6477105
• 关键词: G protein; adrenocorticotropic hormone; autoradiography; biological signal transduction; centrifugation; computer data analysis; corticosteroids; drug adverse effect; fluoxetine; laboratory rat; longitudinal animal study; mental disorder chemotherapy; mood disorders; neuroendocrine system; neurotransmitter receptor; nonhuman therapy evaluation; radioimmunoassay; receptor expression; serotonin; serotonin inhibitor; statistics /biometry; western blottings

Fluoxetine (Prozac ) and other serotonin-selective reuptake blockers (SSRIs) are being increasingly used to treat mood disorders in children. In adults, fluoxetine increases postsynaptic 5HT2A receptor signalling. In contrast, our data reveal that when administered prior to maturation, fluoxetine 5HT2A receptor signal transduction, an effect that is opposite to that produced in adults. However, virtually no preclinical data exist regarding the immediate or long-term changes in 5HT systems due to prepubescent SSRI treatment. The long-term objective of this proposal is to understand the mechanisms and persistence of adaptive changes in 5HT receptor systems produced by pubescent exposure to SSRIs. Because the clinical effectiveness of SSRIs is associated with adaptive changes in 5HT signal transduction, our HYPOTHESIS is that (1) prepubescent fluaxetine treatment will produce different neuroadaptations in postsynaptic 5HT1A and 5HT2A signal transduction than produced by adult treatment, and (2) the effects of prepubescent SSRIs will persist into adulthood and consequently, alter the ability of 5HT systems to respond to subsequent SSRI administration during adulthood. Aim 1 will determine the dose-dependence of fluoxetine-induced changes in postsynaptic 5HT1A and 5HT2A receptors and receptor-mediated neuroendocrine responses, and will establish the treatment dose for subsequent studies. Aim 2 will determine the biochemical mechanisms responsible for fluoxetine-induced adaptation(s) in postsynaptic 5HT1A and 5HT2A receptor systems, by investigating changes in specific components of the signal transduction pathway between 5HT receptors and their respective second messenger enzymes. Aim 3 and Aim 4 will investigate the longer-term effects of prepubescent fluoxetine treatment on changes in postsynaptic 5HT signal transduction. Postsynaptic 5HT1A (aim 3) and 5HT2A (aim 4) receptor systems will be studied with respect to: (1) the persistence of prepubescent fluoxetine-induced 5HT adaptations into adulthood and (2) the regulation of 5HT receptor systems in response to subsequent adult fluoxetine administration following prepubescent exposure. These studies will provide important new information about the mechanisms underlying the immediate and long-term adaptive changes in brain 5HT signalling due to prepubescent fluoxetine treatment. These studies will also elucidate the status of serotonergic function in adults treated previously with SSRIs as juveniles in order to predict how these individuals will respond to subsequent antidepressant treatment as adults. This information is critical to the effective use of SSRIs in treating mood disorders in children and in treating adults treated previously with SSRIs as juveniles.

氟西汀（百忧解）和其他5-羟色胺选择性再摄取阻滞剂（SSRI）越来越多地用于治疗儿童的情绪障碍。 在成年人中，氟西汀增加了突触后5HT2A受体信号传导。 相比之下，我们的数据表明，当在成熟之前给予氟西汀5HT2A受体信号转导，这一作用与成人产生的作用相反。 但是，几乎没有关于由于降级SSRI治疗而导致的5HT系统的直接或长期变化的临床前数据。 该建议的长期目标是了解短柔毛暴露于SSRIS产生的5HT受体系统中适应性变化的机制和持久性。 由于SSRI的临床有效性与5HT信号转导的适应性变化有关，因此我们的假设是（1）（1）氟西汀前的治疗将在突触后5HT1A和5HT2A信号转导中产生不同的神经适应性，与成人治疗产生的效果相比，以及（2）在5HT信号转导的效果，以及（2）在5HT信号转导的效果。在成年期间回应随后的SSRI管理。 AIM 1将确定氟西汀诱导的突触后5HT1A和5HT2A受体的变化的剂量依赖性以及受体介导的神经内分泌反应，并将建立治疗剂量以进行后续研究。 AIM 2将通过研究5HT受体之间的信号转导途径的特定成分的变化，确定氟西汀诱导的后5HT1A和5HT2A受体系统中负责氟西汀诱导的适应性的生化机制。 AIM 3和AIM 4将研究前氟西汀治疗对突触后5HT信号转导变化的长期影响。 突触后5HT1A（AIM 3）和5HT2A（AIM 4）受体系统将在以下方面进行：（1）在成年后氟西汀诱导的5HT适应的持续性，以及（2）对5HT受体系统的调节，响应于随后的成人氟西汀施用后，对5HT受体系统的调节。这些研究将提供有关在青春期前氟西汀治疗引起的脑5HT信号的立即和长期适应性变化的基础机制的重要新信息。 这些研究还将阐明先前用SSRI作为少年治疗的成年人中血清素能功能的状态，以预测这些人将如何应对后续的抗抑郁药作为成年人。 这些信息对于有效利用SSRI在治疗儿童的情绪障碍以及以前用SSRI作为少年治疗的成年人的情绪障碍至关重要。