CLINICAL NEUROBIOLOGY OF SEROTONIN AND ADDICTION

5-羟色胺(5-HT)神经递质系统是研究易损性的重要靶点。 通过适当的生物标记物提高诊断和预后能力，以及 重要的是要治疗这种复杂的疾病。5-羟色胺和兴奋剂翻译中心项目1 成瘾(TCSSA)将检查临床神经生物学的5-羟色胺受体和5-羟色胺受体功能的冲动性和 提示可卡因依赖者和健康对照的反应性内表型，并检查 选择性5-羟色胺再摄取抑制剂/5-HT2cR激动剂艾司匹林的特异性调节作用 非选择性5-HT2R拮抗剂米氮平对人可卡因冲动性和线索反应性的影响 用户。我们假设艾司西普兰和米氮平将显著减少行为实验室 可卡因依赖受试者冲动性和线索反应性的测量。行为影响的预测因子 检查将包括：(1)5-HT2AR和5-HT2cR功能，通过血小板受体结合和 蛋白质分析：(2)特异性5-羟色胺受体和5-羟色胺受体基因多态性。二次量度可卡因 还将检查其使用情况。这些实验将并行研究，以了解5-羟色胺受体和5-羟色胺受体 冲动性和线索反应性的作用机制(项目2)并告知临床前项目 关于对5-羟色胺能治疗有反应的冲动的具体行为测量 药物。加深对主体之间的机制和相互作用的理解 项目1中确定的特征和药物将完善临床前行为方案(项目 2)。此外，了解5-HT2R系统的功能(项目1和2)，表达 特异性5-HT2R基因(核心B)及5-羟色胺能受体操纵对线索反应性的影响 和冲动性测量(项目1)，将有助于深入了解5-羟色胺系统在 成瘾易感性和5-羟色胺信号的潜在神经适应可能参与 戒断、禁欲和治疗反应。 LAV摘要。冲动和对可卡因相关刺激的反应是启动和 维持对可卡因的依赖。这个项目将研究负责这些的大脑机制。 行为。如果对导致冲动的基本大脑机制有更深入的了解 确定这将导致改善对药物滥用和相关行为的治疗。

The serotonin (5-HT) neurotransmitter system is an important target in the quest to understand vulnerability to addiction and relapse, to improve diagnostic and prognostic capabilities with appropriate biomarkers, and importantly to treat this complex disorder. Project 1 of the Translational Center for Serotonin and Stimulant Addiction (TCSSA) will examine the clinical neurobiology of 5-HT^R and 5-HT2cR function in impulsivity and cue reactivity endophenotypes in cocaine-dependent subjects and healthy controls, and examine the specific regulatory effects of the selective serotonin (5-HT) reuptake inhibitor/5-HT2cR agonist escitalopram and the nonselective 5-HT2R antagonist mirtazapine on impulsivity and cue reactivity in human cocaine users. We hypothesize that escitalopram and mirtazapine will significantly reduce behavioral laboratory measures of impulsivity and cue reactivity in cocaine-dependent subjects. Predictors of behavioral effects examined will include: (1) 5-HT2AR and 5-HT2cR function as measured by platelet receptor binding and protein analyses; (2) specific 5-HT^R and 5-HT2CR gene polymorphisms. Secondary measures of cocaine use will also be examined. These experiments will parallel studies to understand the 5-HT^R and 5-HT2CR mechanisms of action in impulsivity and cue reactivity (Project 2) and inform the preclinical projects regarding specific behavioral measures of impulsivity that are responsive to treatment with serotonergic medications. Enhanced understanding of the mechanisms of and the interactions between subject characteristics and medications identified in Project 1 will refine the preclinical behavioral protocols (Project 2). Furthermore, an understanding of the functionality of 5-HT2R systems (Project 1 and 2), expression of specific 5-HT2R genotypes (Core B) and effects of manipulation of serotonergic receptors on cue reactivity and impulsivity measurements (Project 1), will lend significant insight into the role of 5-HT systems in vulnerability to addiction and the potential neuroadaptations in 5-HT signaling that may contribute to withdrawal, abstinence and treatment responses. Lav Abstract. Impulsivity and reactions to cocaine related stimuli are important contributors to initiation and maintenance of cocaine dependence. This project will examine the brain mechanisms responsible for these behaviors. If a greater understanding of the basic brain mechanisms responsible for impulsivity can be determined this will lead to improved treatments for substance abuse and related behaviors.