Serotonin depletion impairs both Pavlovian and instrumental reversal learning in healthy humans

Serotonin is implicated in aversive processing and updating responses to changing environmental circumstances. Optimising behaviour to maximise reward and minimise punishment may require shifting strategies upon encountering new situations. Likewise, emotional reactions to threats are critical for survival yet must be modified as danger shifts from one source to another. Whilst numerous psychiatric disorders are characterised by behavioural and emotional inflexibility, few studies have examined the contribution of serotonin in humans. We modelled both processes in two independent experiments (N = 97), using instrumental and aversive Pavlovian reversal learning paradigms, respectively. Upon depleting the serotonin precursor tryptophan – in a double-blind randomised placebo-controlled design – healthy volunteers showed impairments in updating both behaviour and emotion to reflect changing contingencies. Reversal deficits in each domain, furthermore, were correlated with the extent of tryptophan depletion. These results translate findings in experimental animals to humans and have implications for the neurochemical basis of cognitive inflexibility.

Habenular and striatal activity during performance feedback are differentially linked with state-like and trait-like aspects of tobacco use disorder

The habenula, an epithalamic nucleus involved in reward and aversive processing, may contribute to negative reinforcement mechanisms maintaining nicotine use. We used a performance feedback task that differentially activates the striatum and habenula and administered nicotine and varenicline (versus placebos) to overnight-abstinent smokers and nonsmokers to delineate feedback-related functional brain alterations both as a function of smoking trait (smokers versus nonsmokers) and drug administration state (drug versus placebo). Smokers showed less striatal responsivity to positive feedback, an alteration not mitigated by drug administration, but rather correlated with trait-level addiction severity. Conversely, nicotine administration reduced habenula activity following both positive and negative feedback among abstinent smokers, but not nonsmokers, and increased habenula activity among smokers correlated with elevated state-level tobacco cravings. These outcomes highlight a dissociation between neurobiological processes linked with the dependence severity trait and the nicotine withdrawal state. Interventions simultaneously targeting both aspects may improve currently poor cessation outcomes.