Striatal dopamine D2/D3 receptor regulation of human reward processing and behaviour (Whitehurst, Chika Onwordi, 2025)

Martin Osugo, Matthew B. Wall, Pierluigi Selvaggi, Uzma Zahid, Valeria Finelli, George E. Chapman, Thomas Whitehurst, Ellis Chika Onwordi, Ben Statton, Robert A. McCutcheon, Robin M. Murray, Tiago Reis Marques, Mitul A. Mehta, Oliver D. Howes

Nature Communications, Vol 16, Iss 1, Pp 1-13 (2025)

Available online at this link

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.