Nicotine Vaccine & Nicotine Occupancy of Brain Nicotinic Receptors

描述（由申请人提供）：在过去的三十年中，成瘾领域一直非常关注用于预防和治疗吸烟（尼古丁依赖）的疫苗的开发。基于啮齿动物的临床前研究，推测的作用机制是疫苗接种产生的抗体与尼古丁结合，降低尼古丁穿过血脑屏障并占据中皮质边缘奖赏通路中的烟碱乙酰胆碱受体（nAChR）的速率和量。在本研究中，我们建议在活体吸烟者中验证这种机制。具体而言，我们将使用烟碱激动剂[123 I]5-IA-85380（[123 I]5-IA）和单光子发射计算机断层扫描（SPECT）对大脑22-nAChR进行成像，以确定吸烟者在接种NicVax疫苗前后接受IV尼古丁激发后大脑22-nAChR的尼古丁占用量。我们假设接种疫苗后，尼古丁占据22-nAChR的量将减少至少50%。如果得到证实，这种尼古丁占据nAChR的量的减少将解释为什么接种疫苗的人在吸烟时不太可能上瘾，而目前的吸烟者不会从吸烟中获得同样的满足感。公共卫生相关性吸烟是可预防的死亡和疾病的主要已知原因。尽管吸烟的医疗、经济和社会成本令人衰弱，但人们继续吸烟。这种破坏性行为的持续存在是戒烟治疗不足以帮助吸烟者戒烟的结果。烟碱型乙酰胆碱受体（nAChR）可能是吸烟成瘾的神经化学底物。这些研究将确定尼古丁疫苗如何改变尼古丁向大脑nAChR的递送的大脑机制。由于这些研究导致更好的戒烟治疗，它们将减少当今困扰世界的吸烟相关死亡和疾病的发生率。

DESCRIPTION (provided by applicant): Over the past three decades there has been a strong focus in the field of addiction towards the development of vaccines for the prevention and treatment of tobacco smoking (nicotine dependence). Based on preclinical studies in rodents, the presumed mechanism of action is that the antibodies produced by vaccination, bind to nicotine and decrease the rate and the amount of nicotine that is able to cross the blood-brain barrier and occupy nicotinic acetylcholine receptors (nAChR) in the mesocorticolimbic reward pathway. In the present study, we propose to validate this mechanism in living human smokers. Specifically, we will image brain 22- nAChR using the nicotinic agonist [123I]5-IA-85380 ([123I]5-IA) and single photon emission computed tomography (SPECT) to determine the amount of nicotine occupancy of brain 22-nAChR after an IV nicotine challenge in smokers before and after vaccination with the NicVax vaccine. We hypothesize that after vaccination, the amount of nicotine occupying 22-nAChR will be reduced by at least 50%. If confirmed, this reduction in the amount of nicotine occupying nAChR will explain why, vaccinated individuals will be less likely to become addicted if they smoke, and current smokers will not experience the same satisfaction from smoking. PUBLIC HEALTH RELEVANCE Smoking is the leading known cause of preventable death and disease. Despite the debilitating medical, economic and social costs of cigarette smoking, people continue to smoke. The persistence of this destructive behavior is a consequence of insufficient smoking cessation treatments to assist smokers in their efforts to quit smoking. The nicotinic acetylcholine receptor (nAChR) is a likely neurochemical substrate of the addiction to cigarette smoking. These studies will define the brain mechanism for how the nicotine vaccine alters nicotine delivery to brain nAChR. As these studies lead to better smoking cessation treatments, they will decrease the incidence of smoking-related deaths and disease that plague the world today.