Enhancing Motivated Behavior with Functionally Selective 5-HT2c Receptor Ligands

描述(由申请人提供)：通过功能性选择性5-HT2C受体配体增强动机行为。动力不足是一种令人衰弱和普遍的问题 几种精神障碍的症状，包括精神分裂症和一些情感障碍。虽然众所周知，5-羟色胺影响动机，但其中涉及的机制还不完全清楚。我们对5-羟色胺信号的生理学了解很大程度上来自体外药理学研究或体内麻醉动物实验。然而，要确定5-羟色胺受体信号与动机行为之间的关系，需要在清醒、行为正常的动物身上进行活体实验。这项建议的总体目标是开始分析5-羟色胺受体信号通路和动机之间的具体关系。我们之前发现了一个5-HT2C受体配体(SB242084)，它可以有力地增强野生型小鼠的动机行为，也可以在动机缺陷的转基因小鼠模型中使用。我们已经确定，SB242084介导的行为输出的增强是特定于激励动机的，而不是由运动活动或摄食行为的增加驱动的。这些发现表明，SB242084将是分析5-羟色胺受体在动机行为中所起作用的一个富有成效的起点。先前对麻醉啮齿动物的研究表明，靶向5-HT2C受体的药物调节中脑多巴胺神经元的活动，并影响中脑边缘多巴胺通路中刺激的多巴胺释放水平，中脑边缘多巴胺通路是动机行为的基本回路。因此，我们假设SB242084在行为过程中通过改变中脑边缘通路(特别是伏隔核)中的多巴胺释放来增强激励动机，并建议直接检验这一假设。我们将使用活体技术来测量全身SB242084治疗在动机行为测试期间对伏隔核多巴胺信号动力学的影响。由于5-HT2C受体选择性化合物可以通过作用于受体下游的几个潜在的细胞内信号通路中的一个或多个来发挥其影响，在未来的研究中，我们将研究5-HT2C受体下游的哪些特定分子信号通路是增强动机所必需的。总体而言，我们提出的研究的目标是确定一种精神活性药物在已识别的神经调节回路中的作用机制。我们将获得的数据将为5-羟色胺在动机行为中的作用提供新的线索，并为未来开发新化合物的目标提供关键信息，以改善精神病患者的动机障碍。

DESCRIPTION (provided by applicant): Enhancing Motivated Behavior with Functionally Selective 5-HT2c Receptor Ligands. Deficits in motivation are a debilitating and pervasive symptom of several psychiatric disorders including schizophrenia and some affective disorders. Though it is widely known that serotonin influences motivation, the mechanisms involved are not fully understood. Much of what we know about the physiology of 5-HT signaling comes from in vitro pharmacological studies or in vivo experiments involving anesthetized animals. However, determining the relationship between 5-HT receptor signaling and motivated behaviors requires an in vivo approach in awake, behaving animals. The overall goal of this proposal is to begin the analysis of the specific relationships between 5-HT receptor signaling pathways and motivation. We previously identified a 5-HT2c receptor ligand (SB242084) that robustly enhances motivated behavior in wild-type mice and also in a transgenic mouse model of motivational deficit. We have determined that the enhancement in behavioral output mediated by SB242084 is specific to incentive motivation and not driven by an increase in motor activity or feeding behavior. These finding suggest that SB242084 will be a productive starting point for the analysis of the role that 5-HT receptors play in motivated behaviours. Previous studies in anesthetized rodents have demonstrated that drugs which target the 5-HT2c receptor regulate the activity of midbrain dopamine neurons and also influence the level of stimulated dopamine release in the mesolimbic dopamine pathway, an essential circuit for motivated behaviors. We therefore hypothesize that SB242084 enhances incentive motivation by altering dopamine release in the mesolimbic pathway (specifically in the nucleus accumbens) during behavior and propose to test this hypothesis directly. We will use in vivo techniques to measure the effects of systemic SB242084 treatment on the dynamics of dopamine signaling in the nucleus accumbens during behavioral tests of motivation. Because 5-HT2c receptor selective compounds can exert their influence by acting on one or more of the several potential intracellular signaling pathways that ae downstream of the receptors, in future studies we will examine which of the specific molecular signaling cascades downstream of the 5-HT2c receptor are required for the enhancement of motivation. Overall, the goal of our proposed study is to identify the mechanism of action of a psychoactive drug within an identified neuromodulatory circuit. The data we will obtain will shed new light on the role of serotonin in motivated behavios and provide critical information for the future goal of developing new compounds that will ameliorate the disruption in motivation suffered by psychiatric patients.