Effects of dopamine D2/3 and opioid receptor antagonism on the trade-off between model-based and model-free behaviour in healthy volunteers

Abstract

Human behaviour requires flexible arbitration between actions we do out of habit and actions that are directed towards a specific goal. Drugs that target opioid and dopamine receptors are notorious for inducing maladaptive habitual drug consumption; yet, how the opioidergic and dopaminergic neurotransmitter systems contribute to the arbitration between habitual and goal-directed behaviour is poorly understood. By combining pharmacological challenges with a well-established decision-making task and a novel computational model, we show that the administration of the dopamine D2/3 receptor antagonist amisulpride led to an increase in goal-directed or ‘model-based’ relative to habitual or ‘model-free’ behaviour, whereas the non-selective opioid receptor antagonist naltrexone had no appreciable effect. The effect of amisulpride on model-based/model-free behaviour did not scale with drug serum levels in the blood. Furthermore, participants with higher amisulpride serum levels showed higher explorative behaviour. These findings highlight the distinct functional contributions of dopamine and opioid receptors to goal-directed and habitual behaviour and support the notion that even small doses of amisulpride promote flexible application of cognitive control.

Distinct roles of dopamine and acetylcholine in delay- and effort-based decision making in humans

“…This partially opposing mechanistic relationship between dopaminergic and cholinergic neurotransmission during the effort discounting task is further reflected in changes in choice stochasticity. Previous studies have linked D2 receptor antagonism with increased choice stochasticity (Eisenegger et al, 2014;Mikus et al, 2022).…”

D2/D3 dopamine supports the precision of mental state inferences and self-relevance of joint social outcomes

“…Previous research links tonic dopamine at D2/D3 receptors to efficient encoding of meaningful stimuli and Bayes optimality (Nour et al, 2018), cognitive control (Cools & D’Esposito, 2011), and sustained attention (Saeedi et al, 2016). Under the model-based, model-free control framework (Daw et al, 2005), recent work showed D2/D3 antagonism increased model-based control and decision flexibility (Mikus et al, 2022a) and increased belief flexibility during a trust game (Mikus et al, 2022b). This may be particularly useful in ‘climbing out’ of paranoia, where one is reluctant to take in positive information about others for fear of ‘false reassurance’.…”

“…Following from our preregistered behavioural experiment (Barnby et al, 2020a), we further examine the causal influence of D2/D3 dopamine receptor antagonism on computational mechanisms governing intentional attributions within a simple game theoretic context. Using a formal model of intentional attributions and an iterative Dictator game (Barnby et al, 2020a;2022a), we test the impact of haloperidol, a D2/D3 antagonist, and L-DOPA, a presynaptic dopamine potentiator, on paranoid beliefs using past data (Barnby et al, 2020b).…”

“…Computational modelling is an approach that allows these dynamic cognitive processes to be modelled and has the potential to connect mechanism more effectively to psychiatric phenomenology (Huys et al, 2016; Montague et al, 2012), offering precise accounts of complex behaviour that are more amenable to formal testing, refutation and refinement. Within this framework, dopaminergic alterations have been linked to computational processes such as slower belief updating (Adams et al, 2013; Ashinoff et al, 2022), increased expectations of belief volatility (Diaconescu et al, 2020; Hauke et al, 2023; Reed et al, 2020), and model-based control (Mikus et al, 2022a).…”

“…Following from our preregistered behavioural experiment (Barnby et al, 2020a), we further examine the causal influence of D2/D3 dopamine receptor antagonism on computational mechanisms governing intentional attributions within a simple game theoretic context. Using a formal model of intentional attributions and an iterative Dictator game (Barnby et al, 2020a;2022a), we test the impact of haloperidol, a D2/D3 antagonist, and L-DOPA, a presynaptic dopamine potentiator, on paranoid beliefs using past data (Barnby et al, 2020b). Primarily we assessed whether haloperidol alters key computational processes involved in mental state inferences, allowing distinctions between trait representational changes (priors) and state learning processes (policy flexibility, uncertainty) along each attributional dimension (harmful intent and self-interest).…”