PREPUBESCENT SSRIS & 5HT RECEPTOR SIGNALLING

氟西汀（百忧解）和其他选择性再摄取阻滞剂（SSRIs）越来越多地用于治疗儿童情绪障碍。 在成人中，氟西汀增加突触后5 HT 2A受体信号传导。 相反，我们的数据显示，当在成熟前给药时，氟西汀5 HT 2A受体信号转导，这种作用与成人中产生的作用相反。 然而，几乎没有临床前数据存在的直接或长期的变化，5 HT系统由于青春期前SSRI治疗。 这项建议的长期目标是了解青春期暴露于SSRIs产生的5-HT受体系统适应性变化的机制和持久性。 由于SSRIs的临床有效性与5-HT信号转导的适应性变化有关，我们的假设是：（1）青春期前的氟西汀治疗将在突触后5-HT 1A和5-HT 2A信号转导中产生与成人治疗不同的神经适应，（2）青春期前SSRIs的作用将持续到成年期，因此，改变5-HT系统对成年期后续SSRI给药的反应能力。 目的1将确定氟西汀诱导的突触后5 HT 1A和5 HT 2A受体变化和受体介导的神经内分泌反应的剂量依赖性，并为后续研究确定治疗剂量。 目的2将通过研究5 HT受体及其各自的第二信使酶之间的信号转导通路的特定组分的变化，确定负责氟西汀诱导的突触后5 HT 1A和5 HT 2A受体系统适应的生化机制。 目的3和目的4将研究青春期前氟西汀治疗对突触后5 HT信号转导变化的长期影响。 将研究突触后5 HT 1A（目的3）和5 HT 2A（目的4）受体系统：（1）青春期前氟西汀诱导的5 HT适应性持续至成年期，以及（2）青春期前暴露后，5 HT受体系统对后续成人氟西汀给药的反应调节。这些研究将提供重要的新信息的机制，立即和长期的适应性变化，大脑5羟色胺信号，由于青春期前氟西汀治疗。 这些研究还将阐明在青少年时期接受过SSRI治疗的成年人中，多巴胺能功能的状态，以预测这些个体在成年后对后续抗抑郁治疗的反应。 这些信息对于有效使用SSRIs治疗儿童情绪障碍和治疗以前接受SSRIs治疗的青少年成人至关重要。

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.