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Signalling at dopamine D2/D3 receptors is thought to underlie motivated behaviour, pleasure experiences and emotional expression based on animal studies, but it is unclear if this is the case in humans or how this relates to neural processing of reward stimuli. Using a randomised, double-blind, placebo-controlled, crossover neuroimaging study, we show in healthy humans that sustained dopamine D2/D3 receptor antagonism for 7 days results in negative symptoms (impairments in motivated behaviour, hedonic experience, verbal and emotional expression) and that this is related to blunted striatal response to reward stimuli. In contrast, 7 days of partial D2/D3 agonism does not disrupt reward signalling, motivated behaviour or hedonic experience. Both D2/D3 antagonism and partial agonism induce motor impairments, which are not related to striatal reward response. These findings identify a central role for D2/D3 signalling and reward processing in the mechanism underlying motivated behaviour and emotional responses in humans, with implications for understanding neuropsychiatric disorders such as schizophrenia and Parkinson's disease.

Original publication

DOI

10.1038/s41467-025-56663-7

Type

Journal article

Journal

Nat Commun

Publication Date

21/02/2025

Volume

16

Keywords

Humans, Reward, Receptors, Dopamine D2, Receptors, Dopamine D3, Male, Adult, Female, Double-Blind Method, Corpus Striatum, Cross-Over Studies, Young Adult, Motivation, Emotions, Magnetic Resonance Imaging