Reproducible Human Reward Imaging Phenotypes Exhibit Differential Sensitivity to Dopamine D2 Receptor Antagonism

Sambuco, N.; Lupo, A.; Hawkins, P.; Selvaggi, P.; Antonucci, L. A.; Bertolino, A.; Blasi, G.; Di Palo, P.; Grassi, L.; Grasso, D.; Homan, P.; Leggio, G.; Massari, F.; Monteleone, A. M.; Osugo, M.; Passiatore, R.; Raio, A.; Rampino, A.; Banaschewski, T.; Barker, G.; Bokde, A. L.; Bruehl, R.; Desrivieres, S.; Flor, H.; Garavan, H.; Gowland, P. A.; Grigis, A.; Heinz, A.; Martinot, J.-L.; Martinot, M.-L. P.; Artiges, E.; Nees, F.; Papadopoulos Orfanos, D.; Poustka, l.; Smolka, M. N.; Holz, N. E.; Vaidya, N.; Walter, H.; Whelan, R.; Schumann, G.; Apulian Network on Risk for Psychosis,; Howes, O.

doi:10.64898/2026.05.14.724267

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bioRxiv · 10.64898/2026.05.14.724267

Reproducible Human Reward Imaging Phenotypes Exhibit Differential Sensitivity to Dopamine D2 Receptor Antagonism

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Abstract

Human reward processing varies along cue-centric and outcome-centric axes, but a reproducible mechanistic account of individual variation in incentive salience attribution has been lacking. Using fMRI across five cohorts (N-total=1,251; N1=890; N2=245; N3=34; N4=48; N5=34), we identified two robust imaging phenotypes mirroring sign- and goal-tracking (ST-like, GT-like). ST-like individuals showed dominant ventral striatal responses to reward-anticipation cues and sustained incentive salience attribution; GT-like individuals showed heightened responses to reward outcomes. This distinction was replicable across sites and independent samples. Single-dose and repeated-dose D2/D3 antagonism (risperidone, haloperidol, amisulpride) selectively reduced anticipatory ventral striatal activity in ST, with single-dose antagonism additionally producing a parallel drop in self-reported energy. Instead, D2/D3 partial agonism (aripiprazole) increased anticipatory and reduced outcome-phase responses in GT. In a psychosis cohort, antipsychotic D2 affinity was associated with blunted anticipatory signals and higher negative symptom burden, offering a neuroimaging-driven basis for stratifying patients and predicting response to dopaminergic agents.

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Sambuco, N., Lupo, A., Hawkins, P., Selvaggi, P., Antonucci, L. A., Bertolino, A., Blasi, G., Di Palo, P., Grassi, L., Grasso, D., Homan, P., Leggio, G., Massari, F., Monteleone, A. M., Osugo, M., Passiatore, R., Raio, A., Rampino, A., Banaschewski, T., Barker, G., Bokde, A. L., Bruehl, R., Desrivieres, S., Flor, H., Garavan, H., Gowland, P. A., Grigis, A., Heinz, A., Martinot, J.-L., Martinot, M.-L. P., Artiges, E., Nees, F., Papadopoulos Orfanos, D., Poustka, l., Smolka, M. N., Holz, N. E., Vaidya, N., Walter, H., Whelan, R., Schumann, G., Apulian Network on Risk for Psychosis,, Howes, O.. 2026-05-16. Reproducible Human Reward Imaging Phenotypes Exhibit Differential Sensitivity to Dopamine D2 Receptor Antagonism. https://doi.org/10.64898/2026.05.14.724267

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