Project 3 - Preclinical Studies

摘要：项目3。临床前研究 该中心的临床前项目旨在发现新的治疗方法， 提高戒烟的成功率，并提供更好的基本了解， 尼古丁强化的神经行为过程，为进一步治疗奠定基础 发展在该中心研究工作的初始阶段，临床前项目提供了有希望的新的 帮助戒烟的医学治疗的线索和重要的神经行为机制信息， 有助于指导合理的药物开发，进一步提高戒烟治疗的效果。我们的两 发现，5-羟色胺5 HT 2c拮抗剂氯卡色林和三重单胺递质再摄取的功效 一种抑制剂阿米替丁在显着减少尼古丁自我管理（SA）将提前到人体测试， 中心的临床项目。我们的项目将在中心的下一阶段继续这一进展， 发展尼古丁SA的大鼠模型将用于建立我们发现的基于以下的多种治疗方法： 对烟碱胆碱能、5-HT 2c胆碱能、D1多巴胺能、α2去甲肾上腺素能、H1组胺能和NMDA的作用 多巴胺能受体系统将以三种方式跟进。1)这些有效治疗的组合将 进行评估，以发现哪种药物可以提供额外的治疗效果。2)多样性的不同功效 治疗将在不同的亚群中进行测试，这些亚群基于性别、青少年或尼古丁SA发作的更晚年龄， 低水平与高水平的尼古丁SA，SA的口服消耗方面的参与以及戒烟前后 尼古丁SA的责任3)不同治疗的脑回路机制将通过局部 脑区灌注不同的受体为基础的治疗，看看关键的行动位点是为 成功的治疗这些研究将有助于改进治疗方法，为患者提供量身定制的适应性治疗。 戒烟的人。很明显，不可能有一种单一的治疗方法可以达到所有人， 吸烟者，使他们能够成功戒烟。各种治疗工具箱和进一步了解他们的 作用机制将有助于提供我们中心和一般领域的临床研究，以推进目标 为所有的吸烟者提供戒烟服务。

ABSTRACT: Project 3. Preclinical Studies The preclinical project in the Center has the purpose of discovering new treatments which have promise for enhancing success with tobacco smoking cessation and to provide better basic understanding of the neurobehavioral processes underlying nicotine reinforcement to build a foundation for further treatment development. In the initial phase of the Center's research effort the preclinical project has provided promising new leads for medical treatments to aid smoking cessation and important neurobehavioral mechanistic information to help guide rational drug development for further progress in enhancing smoking cessation therapy. Two of our discoveries, the efficacy of the serotonin 5HT2c antagonist lorcaserin and the triple monoamine transmitter reuptake inhibitor amitifadine in significantly reducing nicotine self-administration (SA) will be advanced to human testing in the clinical project of the Center. Our project will continue this progress in the next phase of the Center's development. The rat model of nicotine SA will be used to build on our discovery of diverse treatments based on actions at nicotinic cholinergic, 5HT2c serotonergic, D1 dopaminergic, α2 nordrenergic, H1 histaminergic and NMDA glutaminergic receptor systems will be followed up in three ways. 1) Combinations of these effective treatments will be evaluated to discover which would provide added therapeutic efficacy. 2) Differential efficacy of the diverse treatments will be tested in different subpopulations based on sex, adolescent or later age of onset of nicotine SA, low vs. high levels of nicotine SA, involvement of oral consummatory aspects of SA and pre or post cessation liability of nicotine SA. 3) The brain circuit mechanisms for the diverse treatments will be characterized through local brain area infusions of the different receptor-based treatments to see where the critical loci of actions are for the successful therapies. These studies will serve to refine the treatments for the tailored and adaptive treatment for smoking cessation in people. It has become clear that there is unlikely to be a single treatment that reaches all smokers to enable them to successfully quit. The diverse toolbox of treatments and further understanding of their mechanisms of action will help provide the clinical studies in our Center and the field in general to advance the goal of smoking cessation for the full variety of smokers.