Cholinergic Enhancement as Treatment for Nicotine Addiction

描述（由申请人提供）：尼古丁成瘾仍然是发达国家可预防死亡的主要原因，仅在美国就估计有43.5万人过早死亡。尽管有有效的药物治疗，但70%至90%的吸烟者在治疗一年内恢复吸烟。因此，开发新型有效的尼古丁依赖药物疗法仍然是一个重要的目标。为了寻找治疗尼古丁成瘾的新方法，我们最近进行了一项使用加兰他明（GAL）治疗吸烟者的初步研究。GAL通过抑制乙酰胆碱酯酶（分解乙酰胆碱的酶）增强胆碱能传递。乙酰胆碱是烟碱型和毒蕈碱型胆碱能受体的内源性神经递质。GAL还能直接增强烟碱乙酰胆碱受体的激活。在我们的研究中，与安慰剂相比，4-da GAL治疗（8毫克/天）减轻了静脉注射（IV）尼古丁的一些主观影响。此外，GAL减少了对香烟的渴望，并提高了在Go - No-Go任务中的表现。这些发现，连同其他临床前和临床研究，支持GAL作为治疗尼古丁成瘾的潜在功效。为了扩展我们的初步研究结果，我们提出了一项双盲、安慰剂对照、受试者之间的研究，将随机分配72名吸烟者接受GAL（8毫克/天，16毫克/天）或安慰剂治疗，共7周。在两周的剂量滴定后，吸烟者将完成一项测量吸烟行为的实验室测试。在接下来的4周治疗阶段，吸烟者将继续服用指定的药物并尝试戒烟。在这个阶段，将获得吸烟行为（自我报告和可替宁）、戒断严重程度和认知表现的测量。据我们所知，这是第一次研究GAL治疗烟草依赖的治疗潜力和作用机制。

DESCRIPTION (provided by applicant): Nicotine addiction continues to be the main cause of preventable death in developed countries, with an estimated 435,000 premature deaths in the U.S. alone. Despite the availability of effective pharmacotherapies, 70 to 90% of smokers resume smoking within a year of treatment. Accordingly, the development of novel and effective nicotine dependence pharmacotherapies continues to be an important goal. In an effort to identify novel therapies for nicotine addiction, we recently conducted a pilot study using galantamine (GAL) as a treatment for smokers. GAL enhances cholinergic transmission by inhibiting acetylcholinesterase, the enzyme that breaks down acetylcholine. Acetylcholine is the endogenous neurotransmitter for the nicotinic and muscarinic type cholinergic receptors. GAL also directly potentiates the activation of nicotinic acetylcholine receptors. In our study, a 4-da GAL treatment (8 mg/day) attenuated some of the subjective effects from intravenous (IV) nicotine when compared with placebo. Furthermore, GAL reduced the craving for cigarettes and improved performance on a Go No-Go task. These findings, together with other preclinical and clinical studies, support the potential efficacy of GAL as a treatment for nicotine addiction. To extend our preliminary findings, we propose a double-blind, placebo-controlled, between-subjects study that will randomize 72 smokers to receive GAL (8 mg/day, 16 mg/day), or a placebo treatment for a total of 7 weeks. Following 2 weeks of dose titration, smokers will complete a laboratory session that measures smoking behavior. In the subsequent 4-week treatment phase, smokers will continue their assigned medication and will attempt to quit smoking. During this phase, measures of smoking behavior (self-report and cotinine), withdrawal severity, and cognitive performance will be obtained. To our knowledge, this is the first study examining the therapeutic potential and the mechanism of action of GAL for the treatment of tobacco dependence.