Systems neuropharmacology of nicotine in aversive learning in humans

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The nicotinic acetylcholine transmitter system regulates aversive learning and memory in animals. Nicotine thereby enhances the coding of aversive experiences in the hippocampus and renders the resulting threat memory persistent. Additionally, nicotine impairs the inhibition of fear, which promotes that fear responses re-occur. Yet, it is unclear if these findings in rodents can be translated into neuropharmacological mechanisms in humans. To date, it has not been studied how nicotine regulates aversive learning and memory in humans.The current project aims to fill this translational gap by delineating how nicotine affects the neural systems that underlie the acquisition and inhibition of aversive learning in humans. To this end, this project employs a placebo-controlled double blind randomized design within a pharmacological fear conditioning model to test the effect of nicotine in two separate studies. First, the acute effect of nicotine on the neural systems involved in fear acquisition and extinction is tested (study 1). In a second step, the impact of chronic nicotine exposure (over four days) on the neural networks mediating extinction learning is tested (study 2). All studies employ a robust and previously established combined cue and contextual conditioning protocol, examining multiple units of analysis, such as neural responses (functional magnetic resonance imaging, fMRI), psychophysiological responses (skin-conductance), as well as subjective ratings.Originating from cellular and behavioral data in animals, the central hypothesis of this project is that acute nicotine enhances aversive learning during fear acquisition. It is moreover expected that nicotine impairs the inhibition of learned fear responses during extinction, in particular after chronic nicotine exposure. These nicotinic effects on aversive learning are expected to involve a hippocampal-centred network, connected to medial prefrontal regions and the amygdala. The anticipated results might thereby delineate how nicotine affects aversive learning in humans and establish the underlying neural basis. The proposed pharmacological challenges on fear and anxiety responses allow for delineation of acute effects of nicotine, as well as adaptions induced by chronic nicotine exposure. Moreover, these results, derived within a translational framework, allow to bridge neuropharmacological findings from animals to humans. These insights might help to understand the neurobiological etiology of anxiety related disorders as well as enable future developments of new pharmacological treatment strategies. As such, this project could mark the starting point to understand how nicotine consumption contributes as a risk factor to the currently high prevalence of anxiety related disorders and inefficient treatment.