Time Course and Potentiation of Fluoxetin Action

描述(由申请人提供) 拟议研究的长期目标是提供新的治疗方法 治疗情绪障碍的方法将更快和更有效 比目前可用的药物更有效。介绍了 选择性5-羟色胺再摄取抑制剂(SSRI)，如氟西汀(百忧解)有 革命性的精神病学。除了它们在治疗中的有效性之外 对于抑郁症，SSRI也被证明对治疗以下几种疾病有效 旧的药物治疗无效的情绪障碍。这些 精神障碍包括焦虑、强迫症、攻击性、进食 精神障碍和经前综合症。然而，滞后时间约为2-3周 从用药开始一直存在到病情好转的第一个迹象 出现。这种延迟的治疗效果是一个严重的问题。其中一些 抑郁症患者的自杀发生在这段滞后时间内。因此，在那里 是非常需要找到更快见效的治疗方法。 支持父母资助的研究表明，使用SSRIs治疗会产生 突触后5-羟色胺A的延迟性同源性脱敏( 5-HT1a)受体在下丘脑。这种脱敏很可能是 通过突触中5-羟色胺水平的增加以及由此导致的 突触后受体过度激活。抑郁症患者的研究 表明SSRIs的治疗效果依赖于 在突触间隙维持高水平的5-羟色胺。5-羟色胺再摄取 机制是终止突触后激活的主要机制 突触间隙中的5-羟色胺受体。然而，从心脏释放5-羟色胺 神经末梢受抑制性5-HT1a自身受体的高度调节 中缝核内5-羟色胺能细胞的胞体和树突 大鼠5-羟色胺能神经末梢抑制性5-HT1B/1D自身受体 前脑区域。因此，总体假设是在SSRI治疗期间， 必须克服5-羟色胺自身受体的抑制影响以允许SSRI 增加突触间隙中5-羟色胺的水平。拟议的研究将 用在体微透析方法研究变化的时间进程 在5-HT1a和5-HT1B/1D自身受体中，从而决定这些 受体在延缓氟西汀引起的大鼠脑缺血发作中的作用 前脑几个区域细胞外5-羟色胺的水平。此外， 研究将调查氟西汀与选择性5-HT1A联合应用 和/或5-HT1B/1D拮抗剂将加速氟西汀诱导的血管紧张素转换酶活性增加 胞外5-羟色胺水平。本研究的结果将提供 使用特定的自身受体拮抗剂的科学基础 使用SSRIs进行辅助治疗，以产生更快速有效的治疗 情绪障碍。

DESCRIPTION (provided by applicant) The long-term goal of the proposed studies is to provide novel therapeutic approaches for the treatment of mood disorders that will work more rapidly and more effectively than the currently available medications. The introduction of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac) has revolutionized psychiatry. In addition to their effectiveness in the treatment of depression, SSRIs also have proven effective for the treatment of several mood disorders for which the older medications were ineffective. These disorders include anxiety, obsessive compulsive disorder, aggression, eating disorders and premenstrual syndrome. However, a lag time of about 2-3 weeks exists from the onset of medication until the first signs of improvement appear. This delayed onset of therapeutic effects is a severe problem. Some of the suicides of depressed patients occur during this lag time. Therefore, there is a great need to find therapeutic approaches that will work more rapidly. Studies supporting the parent grant indicate that treatment with SSRIs produces a delayed-onset, homologous desensitization of post-synaptic serotoninlA( 5-HT1A) receptors in the hypothalamus. This desensitization is most likely mediated by increased levels of 5-HT in the synapse and the resulting over-activation of post-synaptic receptors. Studies in depressed patients indicate that the therapeutic effectiveness of SSRIs is dependent on maintaining high levels of 5-HT in the synaptic cleft. The 5-HT reuptake mechanism is the primary mechanism terminating the activation of post-synaptic receptors by 5-HT in the synaptic cleft. However, the release of 5-HT from the nerve terminals is highly regulated by inhibitory 5-HT1A autoreceptors on the soma and dendrites of the serotonergic cells in the raphe nuclei and by inhibitory 5-HT1B/1D autoreceptors on the serotonergic nerve terminals in forebrain regions. Thus, the overall hypothesis is that during SSRI therapy, the inhibitory influences of 5-HT autoreceptors must be overcome to allow SSRIs to increase the levels of 5-HT in the synaptic cleft. The proposed studies will use in vivo microdialysis approaches to investigate the time courses of changes in both 5-HT1A and 5-HT1B/1D autoreceptors, and thus determine whether these receptors contribute to the delay in onset of fluoxetine-induced increase in extracellular levels of 5-HT in several forebrain regions. In addition, the studies will investigate whether combining fluoxetine with selective 5-HT1A and/or 5-HT1B/1D antagonists will accelerate the fluoxetine-induced increase in extracellular levels of 5-HT. The results of the present studies will provide the scientific foundation for the use of specific autoreceptor antagonists as adjunctive therapy with SSRIs to produce a more rapid and effective therapy of mood disorders.