Project 3 - Preclinical Studies

项目 3 - 临床前研究

• 批准号: 8933618
• 负责人: EDWARD D LEVIN
• 金额: $ 26.34万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8933618
• 关键词: Abstinence; Adolescent; Adult; Affect; Age; Age of Onset; Agonist; Anterior; Area; Brain; Cigarette; Clinical; Clinical Research; Development; Dopamine; Dopamine Antagonists; Female; Foundations; Future; Gender; Glutamate Receptor; Glutamates; Goals; Histamine; Histamine H1 Antagonists; Histamine Receptor; Human; Individual; Infusion procedures; Mediating; Medical; Modeling; N-Methylaspartate; Nicotine; Nicotine Dependence; Nicotinic Receptors; Nucleus Accumbens; Oral; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Population; Process; Psychological reinforcement; Rattus; Research; Self Administration; Serotonin; Sex Characteristics; Smoker; Study models; Subgroup; System; Testing; Tobacco smoking; Treatment Efficacy; Weight Gain; Withholding Treatment; addiction; base; cholinergic; cingulate cortex; drug development; early adolescence; effective therapy; follow-up; individualized medicine; inhibitor/antagonist; innovation; male; monoamine; neural circuit; neurobehavioral; noradrenergic; pre-clinical; preclinical study; receptor; reuptake; sex; smoking cessation; success; therapy development; translational study; treatment effect

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.

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有希望的新疗法 提高戒烟的成功率，并提供对戒烟的更好的基本了解 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产品 有助于戒烟的药物治疗和重要的神经行为机制信息 帮助指导合理的药物开发，以进一步加强戒烟治疗。我们的两个 发现、血清素 5HT2c 拮抗剂氯卡色林和三重单胺递质再摄取的功效 显着减少尼古丁自我给药（SA）的抑制剂阿米替发将进入人体测试 该中心的临床项目。我们的项目将在中心的下一阶段继续取得这一进展 发展。尼古丁 SA 的大鼠模型将用于建立基于我们发现的多种治疗方法的基础上 烟碱胆碱能、5HT2c 血清素能、D1 多巴胺能、α2 去甲肾上腺素能、H1 组胺能和 NMDA 的作用 谷氨酰胺受体系统将通过三种方式进行跟踪。 1）这些有效治疗方法的组合将 进行评估以发现哪一种可以提供额外的治疗功效。 2）不同的功效有差异 将根据性别、青少年或更晚的尼古丁 SA 发病年龄在不同的亚人群中测试治疗方法， 低水平与高水平的尼古丁 SA、涉及 SA 的口腔完善方面以及戒烟前后 尼古丁SA的责任。 3）不同治疗的脑回路机制将通过局部特征来表征 不同基于受体的治疗方法的大脑区域输注，以了解作用的关键位点在哪里 成功的治疗。这些研究将有助于完善针对以下疾病的定制和适应性治疗的治疗方法： 人们戒烟。很明显，不可能有一种单一的治疗方法可以覆盖所有人 帮助吸烟者成功戒烟。多样化的治疗工具箱以及对其的进一步了解 行动机制将有助于在我们中心和整个领域提供临床研究，以推进目标 各种吸烟者的戒烟。