Striatal 5-HT6 receptors, reward and addiction

描述（由申请人提供）：5-羟色胺-6 （5-HT6）受体在纹状体中棘神经元中的表达比人类或大鼠脑中的其他任何地方都要高。因此，它们可以调节血清素对动机行为的很大一部分影响，例如参与学习和维持自然和药物奖励的自我管理。我们之前已经证实5-HT6受体在背侧纹状体和腹侧纹状体中干扰奖励动机学习的获得。我们的核心假设是，由于5-HT6受体在直接途径和间接途径中均有表达，因此这些受体对这两种途径的激活程度相似。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，通过D2受体抑制间接通路神经元。因此，多巴胺打开“打开”和关闭“关闭”开关，这些途径中的差异活动促进动机行为和程序学习，而5-HT6受体的激活通过同时激活这两种途径来减少这种差异活动。为了验证这一假设，我们开发了病毒载体，使我们能够在棘神经元的直接或间接途径中选择性地表达转基因。这些载体是基于dynorphin或enkephalin启动子，分别针对直接和间接途径的中棘神经元。我们已经收集到强有力的证据表明pDYN和pENK载体选择性地靶向这些途径。这为我们提供了在这些通路中增加或减少5-HT6受体表达的关键工具，并测试纹状体5-HT6受体作用的细胞机制。本提案的总体计划是利用这些载体来解开5-HT6受体在背侧和腹侧纹状体直接和间接通路神经元中的作用。我们将使用过表达或RNAi敲低来调节两种途径中的5-HT6受体表达，以检测纹状体离散亚区中的5-HT6受体对自然奖励和药物奖励（可卡因）的工具学习的影响。我们还将研究一旦自我给药建立后，这些受体在每个途径中对可卡因动机的影响，以及它们在面对可卡因服用的负面后果时对强迫性吸毒的影响。这个项目中涉及的假设、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这些不同途径的影响，以便开发出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. PUBLIC HEALTH RELEVANCE: Addiction is a behavioral and brain disease that involves adaptations that interfere with normal flexibility in behavior such that drugs are taken repeatedly and habitually despite negative consequences. We will use state of the art gene manipulations in targeted subgroups of neurons in the rat striatum to understand how 5- HT6 serotonin receptors participate in the acquisition and maintenance of reward motivated learning and cocaine self administration. The goal is to understand how serotonin participates in the adaptations associated with addiction so that we can design treatments to prevent or reverse these changes.