PREPUBESCENT SSRIS & 5HT RECEPTOR SIGNALLING

氟西汀(百忧解)和其他5-羟色胺选择性再摄取阻滞剂(SSRI)正越来越多地被用于治疗儿童的情绪障碍。在成人中，氟西汀增加突触后5HT2A受体信号。相反，我们的数据显示，当在成熟之前给药时，氟西汀5HT2A受体的信号转导，这一效果与成人相反。然而，关于青春期前SSRI治疗对5-羟色胺系统的即时或长期改变，几乎没有临床前数据。这项建议的长期目标是了解青春期暴露于SSRIs的5HT受体系统中适应性变化的机制和持久性。由于SSRIs的临床疗效与5HT信号转导的适应性变化有关，我们的假设是：(1)青春期前氟西汀治疗将在突触后5HT1A和5HT2A信号转导中产生不同于成人治疗的神经适应，(2)青春期前SSRIs的影响将持续到成年期，从而改变5HT系统对成年期SSRI随后给药的反应能力。目的1确定氟西汀诱导的突触后5HT1A和5HT2A受体改变以及受体介导的神经内分泌反应的剂量依赖关系，为后续研究确定治疗剂量。目的2通过研究5羟色胺受体与其各自的第二信使酶之间信号转导通路的特定成分的变化，确定氟西汀诱导突触后5HT1a和5HT2a受体系统适应(S)的生化机制。目的3和目的4将研究青春期前氟西汀治疗对突触后5-羟色胺信号转导的长期影响。突触后5HT1A(AIM 3)和5HT2A(AIM 4)受体系统将在以下方面进行研究：(1)青春期前氟西汀诱导的5HT适应进入成年期的持久性；(2)青春期前暴露后随后给药的成人对5HT受体系统的调节。这些研究将提供重要的新信息，揭示青春期前氟西汀治疗引起的脑内5-羟色胺信号的即刻和长期适应性改变的机制。这些研究还将阐明青少年时期以前接受SSRIs治疗的成年人的5-羟色胺能功能状况，以便预测这些人在成年后对随后的抗抑郁药物治疗会有什么反应。这一信息对于有效使用SSRIs治疗儿童情绪障碍以及在青少年时期治疗以前使用SSRIs治疗的成年人至关重要。

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.