5-HT2R NEUROBIOLOGY IN ANIMAL MODELS OF ADDICTION

成瘾动物模型中的 5-HT2R 神经生物学

• 批准号: 8467831
• 负责人: Kathryn A. Cunningham
• 金额: $ 16.61万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8467831
• 关键词: Abstinence; Agonist; Animal Model; Behavior; Behavior Control; Behavioral; Biological Assay; Biological Availability; Biological Markers; Blood Platelets; Brain; Clinical; Clinical Trials; Clinical assessments; Cocaine; Cocaine Dependence; Cues; Data; Dose; Drug Design; Effectiveness; Equilibrium; Etiology; Exhibits; Floor; Future; Goals; Homo; Human; Impulsivity; Individual; Intervention; Knowledge; Laboratory Study; Ligands; Link; Methodology; Modeling; Molecular; Neurobiology; Outcome; Pattern; Pharmaceutical Preparations; Psychological reinforcement; Psychostimulant dependence; Rattus; Relapse; Research; Rodent; Rodent Model; Role; Schedule; Self Administration; Serotonin; Serotonin Agents; Shapes; Staging; System; Testing; Time; Translations; Treatment Effectiveness; abstracting; addiction; base; behavior measurement; cue reactivity; design; endophenotype; experience; functional status; in vivo; insight; meetings; neurochemistry; neuroimaging; novel; pre-clinical; research study; response; treatment effect; treatment response

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.

5-羟色胺和兴奋剂成瘾转化中心的共同临床问题 （TCSSA）是5-HT神经生物学在冲动性和线索反应性内表型中的作用， 可卡因成瘾项目2将采用和完善冲动和线索反应的行为措施 在大鼠中，将5-HT 2 R和/或5-HT 2cR表达和功能的状态与特异性 行为特征，并检验用M100907（选择性S-HT^R拮抗剂）治疗， WAY 470（选择性5-HT 2cR激动剂）或其组合将使行为和分子模式正常化 的表达。我们将根据反应程度初步确定冲动的内在表型 抑制在差异强化低利率时间表（DRL-20）的任务和线索反应性为基础的 在强迫戒除明确定义的药物期间，药物相关线索强化了杠杆反应 可卡因自我给药模式。我们还将研究冲动的基础水平如何与 吸毒和寻求毒品的进展。与项目3一致，我们建议， 使用选择性同二聚体和/或异二聚体5-HT 2 R配体可能有效。有前途 化合物的体内生物利用度将利用简单的啮齿动物试验以阶梯方法进行评价 这也将作为剂量范围研究，以更深入地评估其在以下方面的有效性： 冲动和线索反应的模型。项目2将直接从临床 神经生物学洞察力（项目1），并采取分子水平的观点来阐述5-HT在靶向 内表型（项目3，核心B）。仔细分析5-HT 2 R和5-HT 2CR表达的状态， 功能和用现存的和新的选择性5-HT 2cR和5-HT 2cR配体或其 组合，在啮齿动物模型中将形成未来假设驱动的神经生物学研究的基本原理， 人类（项目1）和新型选择性靶向血清素能药物的临床评估（项目3）。 拉夫摘要。目前还没有有效的、可获得的治疗兴奋剂成瘾的药物。 available.我们将确定现有的和新设计的药物抑制啮齿动物复发的能力。 模拟人类吸毒的试验。