Nicotine Vaccine & Nicotine Occupancy of Brain Nicotinic Receptors

说明(申请人提供)：在过去的三十年里，成瘾领域的重点是开发预防和治疗烟草吸烟(尼古丁依赖)的疫苗。基于对啮齿动物的临床前研究，推测的作用机制是疫苗产生的抗体与尼古丁结合，降低尼古丁通过血脑屏障的速度和数量，并占据中皮质边缘奖赏通路中的烟碱乙酰胆碱受体(NAChR)。在这项研究中，我们建议在活着的人类吸烟者身上验证这一机制。具体地说，我们将使用尼古丁激动剂[123I]5 IA 85380([123I]5 IA)和单光子发射计算机断层扫描(SPECT)来成像大脑22nAChR，以确定吸烟者在接种NicVax疫苗之前和之后静脉注射尼古丁后大脑22nAChR的尼古丁占有量。我们推测，接种疫苗后，尼古丁占据22nAChR的量将至少减少50%。如果得到证实，尼古丁占据nAChR的数量的减少将解释为什么，接种疫苗的个人如果吸烟，就不太可能上瘾，目前的吸烟者将不会从吸烟中体验到同样的满足感。

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.