Genetic modulation of nicotine effects on emotional on reward processing

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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.