5-HT2R NEUROBIOLOGY IN ANIMAL MODELS OF ADDICTION

血清素和兴奋剂成瘾转化中心的常见临床问题 (TCSSA) 是 5-HT 神经生物学在冲动性和提示反应性内表型中的作用，这些内表型与 可卡因成瘾。项目 2 将采用和完善冲动性和提示反应性的行为测量 在大鼠中，将 5-HT^R 和/或 5-HT2cR 表达和功能的状态与特定的机制联系起来 行为特征，并测试用 M100907（选择性 S-HT^R 拮抗剂）治疗的假设， WAY 470（选择性 5-HT2cR 激动剂）或其组合将使行为和分子模式正常化 的表达。我们将首先根据反应程度识别冲动的内表型 抑制低速率计划（DRL-20）任务的差异强化和基于提示反应性 在强制戒断期间，在明确定义的强制戒断期间，药物相关线索强化了杠杆反应 可卡因自我管理范例。我们还将研究冲动的基本水平如何与 吸毒和寻求毒品的进展。与项目 3 相一致，我们建议在治疗方面取得进展 选择性同二聚体和/或异二聚体 5-HT2R 配体将可能发挥有效性。有前途 将利用简单的啮齿动物测定以阶梯式方法评估化合物的体内生物利用度 这也将作为剂量范围研究，以更深入地评估其有效性 冲动性和提示反应性模型。项目 2 将直接由临床驱动和改编 神经生物学见解（项目 1）并从分子水平角度阐述 5-HT 在靶向治疗中的作用 内表型（项目 3，核心 B）。仔细分析5-HT^R和5-HT2CR表达状态 现有和新型选择性 5-HT^R 和 5-HT2cR 配体或其治疗的功能和效果 啮齿动物模型中的组合将为未来假设驱动的神经生物学研究奠定基础 人类（项目 1）和新型选择性血清素能药物的临床评估（项目 3）。 拉夫摘要。目前尚无有效且易于使用的药物来治疗兴奋剂成瘾 可用。我们将建立现有的和新设计的药物抑制啮齿动物复发的能力 模拟人类吸毒的测定。

common shared clinical question of the Translational Center for Serotonin and Stimulant Addiction (TCSSA) is the role of 5-HT neurobiology in impulsivity and cue reactivity endophenotypes which associate with cocaine addiction. Project 2 will employ and refine behavioral measures of impulsivity and cue reactivity in rats, mechanistically link the status of 5-HT^R and/or 5-HT2cR expression and function to specific behavioral profiles, and test the hypothesis that treatment with M100907 (selective S-HT^R antagonist), WAY 470 (selective 5-HT2cR agonist) or their combination will normalize behavioral and molecular patterns of expression. We will initially identify the endophenotype for impulsivity based upon the degree of response inhibition in the differential reinforcement of low rates schedule (DRL-20) task and for cue reactivity based upon lever responses reinforced by drug-associated cues during forced abstinence from a well-defined cocaine self-administration paradigm. We will also investigate how basal levels of impulsivity interact with the progression of drug-taking and drug-seeking. In concert with Project 3, we propose that gains in treatment effectiveness will be possible with the selective homo- and/or heterodimeric 5-HT2R ligands. Promising compounds will be evaluated for in vivo bioavailability in a stairstep approach utilizing simple rodent assays that will also serve as dose-ranging studies for the more intensive assessment of their effectiveness in models of impulsivity and cue reactivity. Project 2 will be driven and adapted directly from the clinical neurobiology insight (Project 1) and take a molecular-level view to elaborating the role of 5-HT in targeted endophenotypes (Project 3, Core B). Careful analyses of the status of 5-HT^R and 5-HT2CR expression and function and the effects of treatment with extant and novel selective 5-HT^R and 5-HT2cR ligands or their combination, in rodent models will shape the rationale for future hypothesis-driven neurobiological studies in humans (Project 1) and clinical assessments of new selectively-targeted serotonergic drugs (Project 3). Lav Abstract. No effective, accessible medication for the treatment of stimulant addiction is currently available. We will establish the ability of existing and newly designed drugs to suppress relapse in rodent assays which model human drug-taking.