Genetic modulation of nicotine effects on emotional on reward processing

长期以来，成瘾研究中的一种观点认为，烟草依赖的形成是由于尼古丁的增强特性，而这种特性是由纹状体中增加的多巴胺(DA)释放介导的。然而，矛盾的是，像在重度吸烟者中观察到的那样，反复服用尼古丁会使烟碱型乙酰胆碱受体(NAChRs)变得不敏感，进一步服用尼古丁并不会引起DA的释放。各种证据表明，导致S滥用尼古丁的其他机制。首先，动物研究表明，除了尼古丁的直接增强特性外，尼古丁还增强了初级和次级增强剂的奖励效果，这可能是由于它对大脑奖励系统的影响。其次，尼古丁的抗焦虑、缓解压力和改善情绪的作用似乎对持续使用烟草至关重要。讨论的一个可能机制是尼古丁通过将注意力从负性刺激转移到正向刺激来调节影响，这可能是由于它对包括杏仁核和前扣带回(ACC)在内的皮质边缘系统的功能的影响。据我们所知，还没有研究直接在人类大脑系统水平上用脑功能成像来研究尼古丁对情绪和奖励的增强作用。我们建议对80名受试者(40名吸烟者和40名从不吸烟者)在功能磁共振成像过程中进行情绪和动机任务的调查。参与者将在两种情况下进行两次研究，分别使用和不使用尼古丁。主要目的是阐明：1.尼古丁是否改变了杏仁核、ACC、其他边缘和边缘旁结构以及参与视觉空间注意过程的枕颞区和顶区对不愉快和愉快情绪刺激的处理。2.尼古丁放大了大脑奖赏系统中预测奖赏的刺激的加工，并增强了奖赏寻求行为。

A long held view in addiction research is that tobacco dependence develops due to the reinforcing properties of nicotine which are mediated by increased dopamine (DA) release in the striatum. Yet paradoxically, repeated nicotine administration as observed in heavy smokers desensitizes nicotinic acetylcholine receptors (nAChRs) and further nicotine administration does not elicit DA release. Various lines of evidence indicate additional mechanisms that contribute to nicotine s abuse potential. First, animal studies suggest that besides its direct reinforcing properties, nicotine also enhances the rewarding effects of primary and secondary reinforcers, probably due to its effects on the brain reward system. Second, anxiolytic, stress relieving and mood enhancing effects of nicotine seem to be critical for ongoing tobacco use. A possible mechanism discussed is that nicotine modulates affect by biasing attention away from negative and toward positive stimuli which might be due to its effects on the function of the corticolimbic system including amygdala and anterior cingulated cortex (ACC). To our knowledge there are no studies that have directly investigated these mood and reward enhancing effects of nicotine at the level of brain systems in humans with functional brain imaging. We propose to investigate 80 subjects (40 smokers and 40 never-smokers) with an emotional and a motivational task during fMRI. Participants will be studied twice under two conditions, with and without nicotine administration. The main goals are to clarify whether: 1. Nicotine alters processing of unpleasant and pleasant emotional stimuli in the amygdala, ACC, other limbic and paralimbic structures and in occipitotemporal and parietal regions involved in visuospatial attention processes. 2. Nicotine amplifies the processing of stimuli predicting reward in the brain reward system and enhances reward-seeking behavior.