Neuropsychopharmacol：新药物作用大脑多巴胺受体抑制尼古丁上瘾

意大利Aptuit中心研究人员发现，一种名为GSK598809的实验性药物能够阻断大脑中一种多巴胺受体，该多巴胺受体以被证实与尼古丁上瘾有关。

研究小组考察药物对狒狒和小鼠的影响，相关研究论文发表在Neuropsychopharmacology杂志上，当该药物传递到大脑时，这种药物能够减少对尼古丁的渴望。

与大多数成瘾机制类似，尼古丁可与尼古丁乙酰胆碱接受器结果，增加神经传递物的量，脑中的多巴胺增加，产生幸福感和放松感，最后可能会因吸食而有成瘾的现象。

研究人员让狒狒和大鼠对尼古丁上瘾，然后测试GSK598809药物功效。通过进行脑部扫描，能实际观察到尼古丁对大脑的影响。结果已经如此有前途的研究小组报告说，他们现在已经准备好开始进行临床试验的人。

这项新的研究以及以往的研究表明，尼古丁增加多巴胺的释放进入大脑皮质、腹侧纹状体和中脑中是尼古丁成瘾的主要机制。GSK598809并不阻止多巴胺释放进入大脑皮质、腹侧纹状体和中脑，却能降低大脑反应多巴胺的受体（D3受体）的敏感性。

研究人员说，他们相信一旦对GSK598809进行更深入的测试，将有一天会成为人们戒烟的一大利器，因为GSK598809会阻端大脑对尼古丁的渴望，也将有助于防止戒烟者的复发。

doi:10.1038/npp.2012.171
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Occupancy of Brain Dopamine D3 Receptors and Drug Craving: A Translational Approach

Manolo Mugnaini, Laura Iavarone, Palmina Cavallini, Cristiana Griffante, Beatrice Oliosi, Chiara Savoia, John Beaver, Eugenii A Rabiner, Fabrizio Micheli, Christian Heidbreder, Anne Andorn, Emilio Merlo Pich and Massimo Bani

Selective dopamine D3 receptor (D3R) antagonists prevent reinstatement of drug-seeking behavior and decrease the rewarding effects of contextual cues associated with drug intake preclinically, suggesting that they may reduce drug craving in humans. GSK598809 is a selective D3R antagonist recently progressed in Phase I trials. The aim of this study was to establish a model, based on the determination of the occupancy of brain D3Rs (OD3R) across species, to predict the ability of GSK598809 to reduce nicotine-seeking behavior in humans, here assessed as cigarette craving in smokers. Using ex vivo [125I](R)-trans-7-hydroxy-2-[N-propyl-N-(3′-iodo-2′-propenyl)amino] tetralin ([125I]7OH-PIPAT) autoradiography and [11C]PHNO positron emission tomography, we demonstrated a dose-dependent occupancy of the D3Rs by GSK598809 in rat, baboon, and human brains. We also showed a direct relationship between OD3R and pharmacokinetic exposure, and potencies in line with the in vitro binding affinity. Likewise, GSK598809 dose dependently reduced the expression of nicotine-induced conditioned place preference (CPP) in rats, with an effect proportional to the exposure and OD3R at every time point, and 100% effect at OD3R values 72%. In humans, a single dose of GSK598809, giving submaximal levels (72–89%) of OD3R, transiently alleviated craving in smokers after overnight abstinence. These data suggest that either higher OD3R is required for a full effect in humans or that nicotine-seeking behavior in CPP rats only partially translates into craving for cigarettes in short-term abstinent smokers. In addition, they provide the first clinical evidence of potential efficacy of a selective D3R antagonist for the treatment of substance-use disorders.