Genetic modulation of nicotine effects on reward processing

Most people continue to smoke despite their awareness of the danger of smoking and their desire to quit because they are addicted to nicotine. In order to develop more efficient treatments, it is critical to better understand the mechanisms underlying nicotine dependence. At the molecular level, nicotine acts on nicotinic acetylcholine receptors (nAChRs) which are composed of five subunits. Due to the complexity of nAChRs only recent research in cell cultures and animals elucidated the specific properties of various subunits (α2–10 and β2–4) that mediate the sensitivity to nicotine. Especially nicotine’s modulation of activity in mesolimbic DA neurons – originating in the VTA and projecting to the ventral striatum – is fundamental for its reinforcing and ultimately addictive properties. Recent data indicate that nicotine dependence in humans is associated with attenuated mesocorticolimbic reactivity to rewards and that the blunted reactivity to reward can be reversed by acute nicotine. Animal studies revealed nAChR-subunits essential for the crosstalk with the mesolimbic DA system. Interestingly, the genes coding for these nAChR-subunits have also been shown to be associated with differences in human smoking behaviour, e.g. initiation of smoking, vulnerability to nicotine addiction or response to smoking cessation treatments. To bridge the apparent gap between studies on the pharmacodynamics of nicotine in cells and animals on the one hand and genetic epidemiology studies in humans on the other hand, more translational investigations on the pharmacodynamics and pharmacogenetics of nicotine in humans are necessary. This project aims to investigate the effects of nicotine on different aspects of reward processing with functional MRI using tasks that measure instrumental responding for monetary rewards as well as temporal and probabilistic discounting of monetary rewards. The objective of this project is to study how task-related activity in mesocorticolimbic brain regions and connectivity between key structures are affected by nicotine and how these pharmacodynamic effects of nicotine are associated with genetic variation in genes coding the nAChRs.

Researchers:
Andrea Kobiella
Michael N. Smolka

Collaborations:
Mira Bühler, Department of Addictive Behaviour and Addiction Medicine, Central Institute of Mental Health, Mannheim, Germany

Funding:
DFG Grant # SM80/5-2