Dopamine Mechanisms and Receptors in Raphe 5-HT Neurons

描述(由申请人提供)： 中枢5-羟色胺(5-羟色胺)神经传递的减少被认为是起作用的 在严重抑郁障碍(MDD)的病因学中起着重要作用。 增强5-羟色胺功能的治疗策略用于MDD的治疗 症状。基础和临床研究的证据表明，多巴胺(DA) 中缝背核(DRN)的输入，它包含最大的一组 5-羟色胺神经元在正常5-羟色胺的调节中起关键作用 神经传递。此外，帕金森氏症中DA神经元的变性 疾病患者经常与中枢5-羟色胺缺乏有关 神经传递和MDD症状的发生。最后，来自临床的结果 研究表明，类D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水平上调节5-羟色胺系统 可能会对开发更好的MDD治疗方法做出重大贡献。 在过去的两年里，我们研究了多巴胺对兴奋性的影响。 使用脑片细胞内记录技术的DRN 5-羟色胺神经元。 我们在DRN 5-羟色胺中发现了一种新的D2样多巴胺受体诱导兴奋 神经元。这种电生理反应可能代表一种细胞底物 多巴胺通过增强中枢5-羟色胺的神经传递。 在此应用中，使用电生理、药理学和 免疫组织化学技术，我们试图表征详细的细胞 D_1样多巴胺受体激活增强心肌兴奋性的机制 DRN 5-羟色胺神经元。其具体目的是：1)检验类D2的假设 DA受体介导DRN 5-羟色胺神经元的膜去极化 钙依赖的阳离子非选择性电流(IDA)。2)测试 假设从内部存储中释放的钙有助于 激活I‘da*3)以确定所涉及的D2样多巴胺受体亚型(S 在‘DA*4’的激活中)，以阐明介导 通过刺激D2样多巴胺受体来激活‘DA。我们相信结果 从这一提议将更好地理解我们在功能交互中的作用 在DRN的DA和5-羟色胺系统之间，并可能最终有助于 寻找治疗重度抑郁症的新的有效的治疗策略。

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.