5-HT2R NEUROBIOLOGY IN ANIMAL MODELS OF ADDICTION

5-羟色胺和兴奋剂成瘾翻译中心的共同临床问题 (TCSSA)是5-羟色胺神经生物学在冲动和线索反应性内表型中的作用 有可卡因成瘾。项目2将采用并改进冲动和线索反应性的行为测量 在大鼠中，5-羟色胺受体和/或5-HT2cR的表达和功能状态与特定的 并检验M100907(选择性S-羟色胺受体拮抗剂)治疗的假设， Way 470(选择性5-HT2cR激动剂)或它们的组合将使行为和分子模式正常化 表达的方式。我们将根据反应的程度初步确定冲动的内在表型 低速率程序(DRL-20)任务和基于线索反应的差异强化任务中的抑制 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。我们还将调查基本冲动水平如何与 吸毒和寻毒的进展。与项目3一致，我们建议在治疗方面的收益 选择性的同和/或异二聚体5-HT2R配体的有效性是可能的。前景看好 化合物的体内生物利用度将使用简单的啮齿动物分析方法进行阶梯式评估。 这也将作为剂量范围的研究，以便更深入地评估它们在 冲动模型和线索反应性模型。项目2将直接从临床驱动和改编 神经生物学洞察(项目1)并从分子水平阐述5-羟色胺在靶向治疗中的作用 内表型(项目3，核心B)。仔细分析5-羟色胺受体和5-羟色胺受体的表达及 现有的和新的选择性5-羟色胺受体和5-羟色胺受体及其配体的功能和治疗效果 在啮齿动物模型中的结合，将塑造未来以假说为导向的神经生物学研究的基础 人类(项目1)和新的选择性靶向5-羟色胺能药物的临床评估(项目3)。 LAV摘要。目前还没有有效的、可获得的治疗兴奋剂成瘾的药物 可用。我们将建立现有和新设计的药物抑制啮齿动物复发的能力 模拟人类吸毒的化验。

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.