Developing Medication For Tobacco Addiction: NMDA Agents

描述（由申请人提供）：烟草成瘾是一个巨大的公共卫生问题。最近在了解尼古丁对大脑和行为的影响方面取得的进展为推进药物开发提供了机会。NMDA受体的神经传递参与尼古丁的许多作用，并且推测NMDA神经传递的调节可能在烟草成瘾的治疗中有效。我们建议开发和实施人类实验室模型，以筛选有前途的药物，并确定是否与美金刚，一种非竞争性NMDA拮抗剂的NMDA受体系统的调制，在烟草成瘾的治疗中具有有益的效果。为了比较，我们将测试安非他酮，一种抗抑郁药，在治疗烟草成瘾方面具有有效性。住院实验室研究将包括设计用于使用非寻求治疗的尼古丁依赖吸烟者对烟草成瘾的几个维度进行建模的范例。我们将评估安非他酮和美金刚在两个范例中的慢性治疗效果，这两个范例模拟了烟草成瘾的两个主要成分，可以作为药理学调节的目标。在研究1中，我们将模拟吸烟的维持，并评估药物如何影响：早期戒烟，吸烟剥夺和非剥夺吸烟者中香烟的影响，对香烟线索的反应，以及在无限选择条件下和操作条件下吸烟（香烟与金钱选择）。在研究2中，我们将开发一个戒烟吸烟者暴露于香烟诱导的吸烟复发的实验室模型，并将比较暴露于中性或活性香烟刺激后的自我给药行为。在研究3中，我们将使用吸烟复吸模型来评估药物如何影响长期戒断，香烟对剥夺吸烟者的影响，以及戒烟参与者在香烟再次暴露后的自我给药行为。在5年结束时，我们将能够开发实验室模型，用于治疗烟草成瘾的新化合物和/或现有化合物的早期测试，并进一步阐明人类尼古丁依赖的神经生物学，特别是NMDA受体神经传递的贡献。据我们所知，本申请代表了从药物开发的角度系统评价NMDA受体介导的神经传递对尼古丁在人体中作用的贡献的首次尝试。

DESCRIPTION (provided by applicant): Tobacco addiction is an enormous public health problem. Recent advances in understanding the effects of nicotine on the brain and behavior present an opportunity to advance medication development. Neurotransmission at NMDA receptors is involved in many of nicotine's effects and it is postulated that modulation of NMDA neurotransmission may be effective in the treatment of tobacco addiction. We propose to develop and implement human laboratory models to screen promising medications and establish whether modulation of the NMDA receptor system with memantine, a non-competitive NMDA antagonist, has beneficial effects in the treatment of tobacco addiction. For comparison we will test bupropion, an antidepressant with proven efficacy in the treatment of tobacco addiction. Inpatient laboratory studies will include paradigms designed to model several dimensions of tobacco addiction using non-treatment seeking, nicotine-dependent smokers. We will assess the effect of chronic treatment with bupropion and memantine in two paradigms that model two main components of tobacco addiction that can be a target for pharmacological modulation. In Study 1 we will model maintenance of cigarette smoking, and assess how medications affect: early tobacco withdrawal, effects of cigarettes in smoking-deprived and non-deprived smokers, reactivity to cigarette cues, and cigarette smoking under unlimited choice conditions and under operational conditions (cigarettes versus money choice). In Study 2 we will develop a laboratory model of smoking relapse induced by cigarette exposure in abstinent smokers, and will compare self-administration behavior after the exposure to the neutral or active cigarette stimulus. In Study 3, we will use a smoking relapse model to assess how medication affects extended withdrawal, the effects of cigarettes in deprived smokers, and self-administration behavior in abstinent participants following cigarette re-exposure. At the conclusion of 5 years, we will be able to develop laboratory models for early-stage testing of new and/or existing compounds for the treatment of tobacco addiction and to further elucidate the neurobiology of nicotine dependence in humans, particularly the contribution of NMDA receptor neurotransmission. This application represents, to our knowledge, the first attempt to systematically evaluate the contribution of NMDA receptor-mediated neurotransmission on nicotine's action in humans from the perspective of medication development.