Random nicotine delivery: A novel intervention for smokers

描述（由申请人提供）：根据美国疾病控制与预防中心，吸烟与严重的发病率和死亡率有关。仅在美国，吸烟每年就造成约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%的学生报告吸烟。不幸的是，吸烟是一种慢性复发的疾病。事实上，吸烟者在成功戒烟之前会尝试多达20次，即使采用尼古丁替代疗法（NRT），如贴片、口香糖或鼻喷雾剂，戒烟率也可能低至7%。与其他成瘾一样，提示引起的渴望会在尝试戒烟后导致复发。除了提示引起的渴望和复发，成瘾者还遭受药物引起的自然奖励贬值的折磨，证据是老鼠对甜食的反应更少，而等待吸烟的人对金钱奖励的纹状体反应更弱。事实上，那些对自然奖励反应最迟钝的实验对象（老鼠和人类）反过来对药物反应最灵敏。在这里，我们提出了一种新的替代尼古丁稳态输送（即标准贴片），用于治疗香烟成瘾。具体来说，我们建议使用口服薄膜来治疗希望戒烟的吸烟者，在戒烟日期前后随机而不是稳定地提供尼古丁。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、耐受性良好的，并将促进戒烟，从药物中分离尼古丁配对线索，减少药物引起的自然奖励贬值。具体目标1将测试一系列剂量的尼古丁薄膜在人类吸烟者体内的药代动力学和安全性。具体目标2将测试在人类吸烟者戒烟前后接受随机和稳态尼古丁治疗是否有助于戒烟。最后，Specific Aim 3将使用功能磁共振成像和公开的程序来测试随机尼古丁递送是否也会减少神经（纹状体）对尼古丁配对线索的反应，并增强神经对替代货币奖励的反应。如果我们的随机传递假说得到证实，这种新方法将彻底改变药物滥用和成瘾的治疗。

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.