Systems neuropharmacology of nicotine in aversive learning in humans
Human Cognitive and Systems Neuroscience
Final Report Abstract
The nicotinic acetylcholine transmitter system is important for regulating learning and memory in animals. Nicotine affects synaptic plasticity in the hippocampus by acting on β2-containing nicotinic acetylcholine receptors (nAChRs). This affects memory processes like short-term and long-term potentiation. In animal experiments, systemic nicotine infusion alters neural activity in brain regions essential for emotional learning, such as the amygdala, hippocampus, and medial prefrontal cortex (mPFC). These interactions enhance the salience and memory for aversive experiences, while impairing the discrimination between threatening and safe stimuli. Our previous research further indicated that human smokers exhibit deficits in associative memories that enabled to distinguish learned threats from safety compared to non-smokers. Yet, it is unknown if a causal neuropharmacological mechanism of nicotine underlies this phenomenon. This project aimed to bridge this translational gap by exploring how nicotine affects neural systems involved in the acquisition and extinction of aversive learning in humans through a placebo-controlled, double-blind randomized design within a pharmacological fear conditioning model. We pursued two main objectives: 1) to investigate the acute effects of nicotine on neural pathways related to fear acquisition and extinction, and 2) to assess the impact of chronic nicotine exposure on extinction learning. Despite challenges posed by the COVID-19 pandemic, we successfully conducted a pharmacological fMRI study with 88 participants and a large online study involving 202 smokers. The published results from both studies, form the foundation for a new research trajectory which was followed-up by rhe PhD student in a competitive grant for post-doctoral funding at the University Medical Center in Hamburg.
Publications
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Acquisition of threat responses are associated with elevated plasma concentration of endocannabinoids in male humans. Neuropsychopharmacology, 47(11), 1931-1938.
Weisser, Smilla; Mueller, Madeleine; Rauh, Jonas; Esser, Roland; Fuss, Johannes; Lutz, Beat & Haaker, Jan
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Smokers show increased fear responses towards safety signals during fear generalization, independent from acute smoking. Scientific Reports, 12(1).
Mueller, Madeleine; Weisser, Smilla; Rauh, Jonas & Haaker, Jan
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Nicotine reduces discrimination between threat and safety in the hippocampus, nucleus accumbens and amygdala. Translational Psychiatry, 14(1).
Mueller, Madeleine; Fadai, Tahmine; Rauh, Jonas & Haaker, Jan
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Observational threat learning influences costly avoidance behaviour in healthy humans. Scientific Reports, 14(1).
Mueller, Madeleine; Cohen, Oded; Shechner, Tomer & Haaker, Jan
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Downstream effects of observational threat learning: Generalization and reversal learning across development. Behaviour Research and Therapy, 184, 104670.
Cohen, Oded; Skversky-Blocq, Yael; Mueller, Madeleine; Haaker, Jan & Shechner, Tomer
