Striatal 5-HT6 receptors, reward and addiction

描述（由申请人提供）：5-羟色胺-6（5-HT 6）受体在纹状体中型多刺神经元中的表达比在人脑或大鼠脑中的任何其他地方都要高。因此，它们被定位为介导显着比例的血清素对动机行为的影响，例如参与学习和维持自然和药物奖励的自我管理。我们以前建立了5-HT 6受体干扰获得奖励动机的学习在背侧和腹侧纹状体。我们的核心假设是，由于5-HT 6受体在直接和间接途径中多刺神经元中表达，这些受体以相似的程度激活这两种途径。这与多巴胺的作用相反，多巴胺通过D1受体激活直接通路神经元，并通过D2受体抑制间接通路神经元。因此，多巴胺打开“开”开关并关闭“关”开关，这些通路中的差异活性促进动机性行为和程序性学习，而5-HT 6受体激活通过同时激活两条通路来降低这种差异活性。为了验证这一假设，我们已经开发了病毒载体，使我们能够在直接或间接途径中选择性地表达转基因多刺神经元。这些载体基于强啡肽或脑啡肽启动子，其分别差异性地靶向直接和间接途径的中型多棘神经元。我们已经收集了强有力的证据表明pDYN和pENK载体选择性地靶向这些通路。这为我们提供了关键的工具，以增加或减少5-HT 6受体表达在这些途径的差异，并测试纹状体5-HT 6受体作用的细胞机制。该建议的总体计划是使用这些载体解开5-HT 6受体在背侧和腹侧纹状体的直接和间接通路神经元中的作用。我们将使用过表达或RNAi敲低来调节任一途径中的5-HT 6受体表达，以检查纹状体离散亚区中的5-HT 6受体对工具性学习的自然奖励以及药物奖励（可卡因）。我们还将研究这些受体在每一个途径上的可卡因的动机，一旦自我管理的影响，以及他们的强迫性吸毒的负面后果，以可卡因服用面对的效果。这个项目所涉及的假设、策略和工具都是高度创新的。这项工作的长期目标是了解血清素对药物滥用中这些不同途径的影响，以便开发更好的成瘾治疗方法。

DESCRIPTION (provided by applicant): Serotonin-6 (5-HT6) receptors are more heavily expressed in striatal medium spiny neurons than anywhere else in human or rat brain. Therefore, they are positioned to mediate a significant proportion of serotonin's effect on motivated behavior, such as is involved in learning and maintenance of self-administration of natural and drug rewards. We previously established that 5-HT6 receptors interfere with the acquisition of reward motivated learning in both dorsal and ventral striatum. Our core hypothesis is that, since 5-HT6 receptors are expressed in both the direct and indirect pathway medium spiny neurons, these receptors activate both pathways to a similar extent. This opposes the action of dopamine, which activates direct pathway neurons via D1 receptors and inhibits indirect pathway neurons via D2 receptors. Thus, dopamine turn on the "on" switch and off the "off" switch, and differential activity in these pathways promotes motivated behavior and procedural learning whereas 5-HT6 receptor activation reduces this differential activity by activating both pathways simultaneously. In order to test this hypothesis we have developed viral vectors that allow us to express transgenes selectively in the direct or indirect pathway medium spiny neurons. These vectors are based on the dynorphin or enkephalin promoter, which differentially target the direct and indirect pathway medium spiny neurons, respectively. We have collected strong evidence that the pDYN and pENK vectors target these pathways selectively. This provides us with key tools to increase or decrease 5-HT6 receptor expression in these pathways differentially and to test the cellular mechanism underlying striatal 5-HT6 receptor actions. The overall plan for this proposal is to use these vectors to disentangle the role of 5-HT6 receptors in direct and indirect pathway neurons of both dorsal and ventral striatum. We will use either overexpression or RNAi knockdown to modulate 5-HT6 receptor expression in either pathway to examine 5-HT6 receptors in discrete subregions of striatum on instrumental learning for a natural reward as well as a drug reward (cocaine). We will also examine the impact of these receptors in each pathway on motivation for cocaine once self-administration is established, and their effect on compulsive drug taking in the face of negative consequences to cocaine taking. The hypothesis, strategy, and tools involved in this project are all highly innovative. The long-term goal of this work is to understand the impact of serotonin on these distinct pathways in drug abuse so that better treatments for addiction can be developed.