PREPUBESCENT SSRIS & 5HT RECEPTOR SIGNALLING

青春期前SSRIS

• 批准号: 6031352
• 负责人: GEORGE BATTAGLIA
• 金额: $ 23.97万
• 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/6031352
• 关键词: G protein; adrenocorticotropic hormone; autoradiography; biological signal transduction; centrifugation; 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）和其他血清素选择性再摄取阻滞剂（SSRI）越来越多地用于治疗儿童情绪障碍。 在成人中，氟西汀会增加突触后 5HT2A 受体信号传导。 相比之下，我们的数据表明，在成熟前施用时，氟西汀 5HT2A 受体信号转导，这种作用与成人中产生的作用相反。 然而，实际上没有关于青春期前 SSRI 治疗导致 5HT 系统立即或长期变化的临床前数据。 该提案的长期目标是了解青春期暴露于 SSRI 所产生的 5HT 受体系统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相关，因此我们的假设是（1）青春期前氟西汀治疗将在突触后 5HT1A 和 5HT2A 信号转导中产生与成人治疗不同的神经适应，以及（2）青春期前的 SSRI 会持续到成年，因此会改变 5HT 系统对成年后后续 SSRI 给药的反应能力。 目标 1 将确定氟西汀诱导的突触后 5HT1A 和 5HT2A 受体变化以及受体介导的神经内分泌反应的剂量依赖性，并将确定后续研究的治疗剂量。 目标 2 将通过研究 5HT 受体与其各自的第二信使酶之间信号转导途径特定成分的变化，确定氟西汀诱导突触后 5HT1A 和 5HT2A 受体系统适应的生化机制。 目标 3 和目标 4 将研究青春期前氟西汀治疗对突触后 5HT 信号转导变化的长期影响。 将研究突触后 5HT1A（目标 3）和 5HT2A（目标 4）受体系统：(1) 青春期前氟西汀诱导的 5HT 适应到成年期的持续性，以及 (2) 5HT 受体系统对随后成年期的反应的调节青春期前暴露后给予氟西汀。这些研究将提供关于青春期前氟西汀治疗导致大脑 5HT 信号传导立即和长期适应性变化的机制的重要新信息。 这些研究还将阐明在青少年时期接受过 SSRI 治疗的成年人的血清素能功能状态，以便预测这些个体在成年后对后续抗抑郁治疗的反应。 这一信息对于有效使用 SSRI 治疗儿童情绪障碍和治疗曾在青少年时期接受 SSRI 治疗的成年人至关重要。