Project 3 - Preclinical Studies

摘要：项目3.临床前研究 该中心的临床前项目的目的是发现新的治疗方法，这些方法有望 促进成功戒烟，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 帮助戒烟的药物治疗的线索和重要的神经行为机制信息 帮助指导合理的药物开发，以促进戒烟治疗的进一步进展。我们的两个人 5-羟色胺5-HT2c拮抗剂氯酪蛋白的发现、疗效和三重单胺递质再摄取 显著减少尼古丁自我给药(SA)的抑制剂阿米替法丁将于年进入人体试验 该中心的临床项目。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的大鼠模型将被用来建立在我们发现的多种治疗方法的基础上 烟碱型胆碱能、5-羟色胺能、D_1多巴胺能、α_2去甲肾上腺素能、H_1组胺能和N-甲基-D-天冬氨酸的作用 谷氨酰胺能受体系统将通过三种方式进行追踪。1)这些有效治疗方法的组合将 进行评估，以发现哪种药物将提供额外的治疗效果。2)不同品种的疗效不同 治疗将根据性别、青少年或更晚的尼古丁SA发病年龄在不同的人群中进行测试， 低水平与高水平的尼古丁SA，涉及SA的口服消耗性方面以及戒烟前后 尼古丁SA的责任。3)不同治疗方法的脑回路机制将通过局部表征 不同的基于受体的治疗的脑区注射，以了解在哪里的关键作用场所 成功的治疗方法。这些研究将有助于完善针对以下疾病的量身定制和适应性治疗 在人们中戒烟。很明显，不太可能有一种单一的治疗方法可以覆盖所有人 让吸烟者能够成功戒烟。不同的治疗工具箱及其对其的进一步理解 作用机制将有助于在我们的中心和整个领域提供临床研究，以推进这一目标 为所有类型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.