Dopamine Mechanisms and Receptors in Raphe 5-HT Neurons

描述（由申请人提供）： 中枢5-羟色胺（5-HT）神经传递的减少被认为是 在重性抑郁症（MDD）的病因学中起重要作用。 增强5-HT功能的治疗策略用于治疗MDD 症状基础和临床研究表明，多巴胺（DA） 输入到中缝背核（DRN），其中包含最大的一组 5-HT神经元在正常5-HT的调节中起关键作用 神经传递此外，帕金森氏症中DA神经元的退化 疾病患者通常与中枢5-HT缺陷相关 神经传递和MDD症状的发作。最后，临床结果 研究表明，D1-样DA受体激动剂和DA释放剂增强 选择性5-羟色胺再摄取抑制剂（SSRIs）的抗抑郁作用。 因此，了解DA如何在DRN水平调节5-HT系统， 可能对开发更好的MDD治疗方法有重大贡献。 在过去的两年里，我们研究了DA对兴奋性的影响， 在脑片中使用细胞内记录技术的DRN 5-HT神经元。 我们在DRN 5-HT中发现了一种新的D2样DA受体 神经元这种电生理反应可能代表了一种细胞基质 DA通过此途径增强中枢5-HT神经传递。 在该应用中，使用电生理学、药理学和 免疫组织化学技术，我们试图描述详细的细胞 D1-like DA受体激活增加神经元兴奋性的机制 DRN 5-HT神经元。具体目的是：1）检验D2样 多巴胺受体介导DRN 5-HT神经元膜去极化 钙依赖性阳离子非选择性电流（IDA）。2)测试 假设钙从内部储存释放有助于 * 3）鉴定涉及的D2样DA受体亚型 * 4）为了阐明介导DA受体活化的信号传导机制， 通过D2样DA受体刺激来激活DA。我们相信结果 从这一建议将更好地了解在功能的相互作用 DA和5-HT系统之间的DRN，并可能最终有助于 寻找新的和有效的治疗策略，为抑郁症。

DESCRIPTION (provided by applicant): A reduction in central serotenergic (5-HT) neurotransmission is thought to play an important role in the etiology of major depression disorders (MDD). Treatments strategies that enhance 5-HT function are used to treat MDD symptoms. Evidence from basic and clinical studies indicates that dopamine (DA) input to the dorsal raphe nucleus (DRN), which contains the largest group of 5-HT neurons, plays a key role in the regulation of normal 5-HT neurotransmission. Furthermore, a degeneration of DA neurons in Parkinson's disease patients is frequently associated with a deficit in central 5-HT neurotransmission and the onset of MDD symptoms. Finally, results from clinical studies show that D,-like DA receptor agonists and DA releasing agents enhance the antidepressant effect of selective serotonin reuptake inhibitors (SSRIs). Thus, understanding how DA regulates the 5-HT system at the level of the DRN may contribute significantly to the development of better treatment for MDD. Over the past two years we have studied the effect of DA on the excitability of DRN 5-HT neurons using the intracellular recording technique in brain slices. We have identified a novel D2-like DA receptors induced excitation in DRN 5-HT neurons. This electrophysiological response may represent a cellular substrate by which DA enhances central 5-HT neurotransmission. In this application, using electrophysiological, pharmacological and immunohistochemical techniques, we seek to characterize the detailed cellular mechanism by which D,-like DA receptor activation increases the excitability of DRN 5-HT neurons. The specific Aims are 1) To test the hypothesis that D2-like DA receptors induced membrane depolarization in DRN 5-HT neurons is mediated by a calcium-dependent cation non-selective current (IDA). 2) To test the hypothesis that calcium release from internal stores contributes to the activation of i'DA* 3) To identify the D2-like DA receptor subtypes(s) involved in the activation of 'DA* 4) To elucidate the signaling mechanism that mediates the activation of 'DA by D2-like DA receptor stimulation. We believe results from this proposal will better our understanding in the functional interaction between DA and 5-HT systems in the DRN, and may ultimately contribute to the search of novel and effective treatments strategies for major depression.