CLINICAL NEUROBIOLOGY OF SEROTONIN AND ADDICTION

5-羟色胺（5-HT）神经递质系统是探索脆弱性的重要目标 成瘾和复发，用适当的生物标志物提高诊断和预后能力， 治疗这种复杂的疾病。5-羟色胺和兴奋剂转化中心项目1 成瘾（TCSSA）将检查5-HT^R和5-HT 2cR在冲动性中的临床神经生物学功能， 提示可卡因依赖受试者和健康对照者的反应性内表型，并检查 选择性5-羟色胺再摄取抑制剂/5-HT 2cR激动剂艾司西酞普兰的特异性调节作用 和非选择性5-HT 2 R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.我们假设艾司西酞普兰和米氮平会显著降低行为实验室检查结果， 可卡因依赖受试者的冲动性和线索反应的措施。行为效应的预测因子 检查将包括：（1）5-HT 2AR和5-HT 2cR功能，通过血小板受体结合测定， （2）特异性5-HT^R和5-HT 2CR基因多态性。可卡因的次级措施 使用也将被审查。这些实验将平行研究，以了解5-HT 2 R和5-HT 2CR 冲动和线索反应的作用机制（项目2），并为临床前项目提供信息 关于冲动性的特定行为测量，这些测量响应于用多巴胺能神经递质治疗， 药物治疗加强对主题的机制和主题之间的相互作用的理解 项目1中确定的特征和药物将完善临床前行为方案（项目1）。 2）。此外，了解5-HT 2 R系统的功能（项目1和2），表达 特异性5-HT 2 R基因型（核心B）和操纵肾上腺素能受体对线索反应性的影响 和冲动性测量（项目1），将为深入了解5-HT系统在 成瘾的脆弱性和5-HT信号传导中的潜在神经适应可能有助于 戒断、禁欲和治疗反应。 拉夫摘要。冲动和反应可卡因相关的刺激是重要的贡献者， 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。如果能更好地理解冲动的基本大脑机制， 确定这将导致改善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.