Random nicotine delivery: A novel intervention for smokers

描述(申请人提供)：根据疾控中心的说法，吸烟与严重的发病率和死亡率有关。仅在美国，吸烟每年造成约44.3万人死亡，每年给国家造成近2000亿美元的损失。在美国，大约20%的成年人吸烟，到12年级时，42%的学生报告说曾经吸烟。不幸的是，吸烟是一种慢性旧病复发。事实上，吸烟者在成功戒烟之前会尝试多达20次，戒烟率可能低至7%，即使在使用贴片、口香糖或鼻喷雾进行尼古丁替代治疗(NRT)后也是如此。与其他上瘾一样，线索诱导的渴望在戒烟尝试后会导致复发。除了线索诱导的渴望和复发，吸毒者还遭受药物导致的自然奖励贬值，这一点在老鼠身上表现为对甜食的反应减弱，在等待吸烟的人类身上表现为对金钱奖励的纹状体反应减弱。事实上，那些被发现对自然奖赏最不敏感的受试者(老鼠和人类)，反过来对药物最敏感。在这里，我们提出了一种新的替代尼古丁稳态递送(即标准贴片)的方法，用于治疗香烟成瘾。具体地说，我们建议使用口服膜来治疗希望戒烟的吸烟者，在戒烟日期之前和之后随机而不是稳定地注射尼古丁。基于有希望的临床前和临床数据，我们假设，相对于稳态给药，随机尼古丁给药将是安全的，耐受性良好，将促进戒烟，将尼古丁与药物配对的线索从药物中分离出来，并减少药物诱导的自然奖励贬值。特定目标1将测试一系列剂量的尼古丁薄膜在人类吸烟者中的药代动力学和安全性。特定目标2将测试当吸烟者在戒烟日期之前和之后接受随机和稳定的尼古丁注射时，是否有助于戒烟。最后，《特定目标3》将使用功能磁共振成像和已公布的程序来测试随机发放尼古丁是否也会降低神经(纹状体)对尼古丁配对线索的反应，并增强神经对另一种金钱奖励的反应。如果我们的随机递送假说得到证实，这种新的方法将彻底改变药物滥用和成瘾的治疗方法。

DESCRIPTION (provided by applicant): According to the CDC, cigarette smoking is associated with profound morbidity and mortality. In the United States alone, cigarette smoking is responsible for about 443,000 deaths per year and it costs the nation nearly $200 billion annually. About 20% of all adults smoke in the United States and by 12th grade, 42% of students report having smoked. Unfortunately, cigarette smoking is a disease of chronic relapse. Indeed, smokers will make as many as 20 quit attempts before they are successful and abstinence rates can be as low as 7%, even following nicotine replacement therapy (NRT) with the patch, gum, or nasal spray. As with other addictions, cue-induced craving contributes to relapse following a quit attempt. Along with cue-induced craving and relapse, addicts also suffer from drug-induced devaluation of natural rewards as evidenced by less responding for a sweet in rats and a weaker striatal response to monetary rewards in humans waiting to smoke. Indeed, those subjects (rats and humans) found least responsive to the natural reward are, in turn, most responsive to drug. Here we propose a novel alternative to the steady-state delivery of nicotine (i.e., to the standard patch), for the treatment of cigarette addiction. Specifically, we propose t use an oral film to treat smokers wishing to quit with random, rather than steady-state, delivery of nicotine prior to and following the quit date. On the basis of promising preclinical and clinica data, we hypothesize that, relative to steady state delivery, random nicotine delivery will be safe well-tolerated, and will facilitate smoking cessation, dissociation of nicotine-paired cues from drug, and a reduction in drug-induced devaluation of natural rewards. Specific Aim 1 will test the pharmacokinetics and safety of a range of doses of the nicotine film in human smokers. Specific Aim 2 will test whether smoking cessation is facilitated when human smokers are treated with random vs. steady-state delivery of nicotine before and after the quit date. Finally, Specific Aim 3 will use fMRI and published procedures to test whether random nicotine delivery also will reduce the neural (striatal) response to nicotine-paired cues and augment the neural response to an alternative monetary reward. If our random delivery hypothesis is confirmed, this novel approach will revolutionize treatment of substance abuse and addiction.