Cholinergic transmission abnormalities associated with smoking behavior in humans

项目摘要/摘要 近几十年来，吸烟在美国总人口中的流行率直线下降 但有一部分吸烟者一直无法戒烟。因为尼古丁作用于构成大脑一部分的感受器 胆碱能系统，调节胆碱能受体信号的药物已经开发出来， 实施，并被证明是有效的戒烟。然而，人类吸烟者对此知之甚少。 由于缺乏工具，突触后受体功能以外的体内胆碱能系统的完整性 特别是胆碱能传递的成像。更好地了解突触前胆碱能完整性可能 提供新的药物靶点，可与目前批准的作用于 突触后受体。这一策略在长期吸烟者中可能特别有成效 治疗手段还不足以实现完全戒烟。在这里，我们将使用新开发的 放射性示踪剂[18F]VAT结合正电子发射断层扫描(PET)成像不同的分子 靶蛋白，囊泡乙酰胆碱转运体(VAChT)；VAChT是突触前的，对胆碱能具有特异性 囊泡，因此可以提供一种测量终末胆碱能储存的方法，直接与 变速箱。我们的初步数据显示，[18F]增值税：目前在石溪正在常规使用 大学，显示出重测重复性的初步证据，并具有足够的敏感度来检测群体 健康人群和临床人群之间的差异，包括吸毒成瘾。在此应用程序中，我们满足 尖端基础研究奖(CEBRA)标准通过测试创新和重要的假设， 由于之前突触前胆碱能示踪剂的不可用，几乎没有可用的人类数据， 吸烟者与不吸烟者相比，胆碱能传递较低。我们将研究14名吸烟者和 14名非吸烟者与[18F]VAT相匹配，我们将关联产生的突触前胆碱能完整性数据， 在纹状体和选定的前额叶皮质区域以[18F]增值税总分配体积(VT)为指标， 和吸烟的速度，在实验室自我管理的范例中，并与慢性 吸烟的严重性。这项研究的结果还将提供增加吸烟所需的基础数据 调查以及潜在地将这种新示踪剂用于其他成瘾，与以下目标一致 CEBRA机制。最后，结果可能会为药物开发提供新的途径，以帮助 上瘾的吸烟者实现持久的戒烟。

PROJECT SUMMARY/ABSTRACT In recent decades, the prevalence of cigarette smoking has plummeted in the general population of the United States, but a subset of smokers has been unable to quit. As nicotine acts at receptors that form part of the brain cholinergic system, medications that modulate cholinergic receptor signaling have been developed, implemented, and shown to be efficacious for smoking cessation. Yet, little is known in human smokers about the integrity of the cholinergic system in vivo beyond postsynaptic receptor functioning, due to a lack of tools for imaging cholinergic transmission specifically. A better understanding of presynaptic cholinergic integrity could provide novel medication targets that can be used adjunctively with currently approved medications acting at postsynaptic receptors. This strategy could be especially fruitful among chronic smokers for whom available therapeutics have been insufficient to accomplish complete cessation. Here, we will use the newly-developed radiotracer [18F]VAT in conjunction with positron emission tomography (PET) to image a different molecular target, the vesicular acetylcholine transporter (VAChT); VAChT is presynaptic and specific to cholinergic vesicles, and therefore can provide a measure of cholinergic storage in terminals that directly relates to transmission. Our preliminary data demonstrate that [18F]VAT: is currently in routine use at Stony Brook University, shows initial evidence for test-retest reproducibility, and has sufficient sensitivity to detect group differences between healthy and clinical populations, including drug addiction. In this application, we satisfy the Cutting-Edge Basic Research Awards (CEBRA) criteria by testing the innovative and significant hypothesis, for which there is little available human data due to the previous unavailability of presynaptic cholinergic tracers, that smokers have lower cholinergic transmission compared with non-smokers. We will study 14 smokers and 14 matched non-smokers with [18F]VAT, and we will correlate the resulting presynaptic cholinergic integrity data, indexed as [18F]VAT total distribution volume (VT) in striatal and select prefrontal cortical regions, with the amount and speed of cigarette smoking in a laboratory self-administration paradigm, and with measures of chronic smoking severity. Results of this study will also provide the foundational data needed to take on larger smoking investigations as well as potentially apply this new tracer for use in other addictions, consistent with the goals of the CEBRA mechanism. Finally, results can potentially inform new avenues for medication development to help addicted smokers achieve lasting cigarette abstinence.