Reproducible human reward imaging phenotypes exhibit differential sensitivity to dopamine D2 receptor antagonism.

Human reward processing varies along cue-centric and outcome-centric axes, but the mechanistic basis of individual variation in incentive salience attribution remains incompletely characterized. Here we show, using fMRI across five cohorts (N-total = 1251; N1 = 890; N2 = 245; N3 = 34; N4 = 48; N5 = 34), two reproducible 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.
Mental Health
Care/Management

Authors

Sambuco Sambuco, Lupo Lupo, Hawkins Hawkins, Selvaggi Selvaggi, Antonucci Antonucci, Bertolino Bertolino, Blasi Blasi, Di Palo Di Palo, Grassi Grassi, Grasso Grasso, Homan Homan, Leggio Leggio, Massari Massari, Monteleone Monteleone, Osugo Osugo, Passiatore Passiatore, Raio Raio, Rampino Rampino, Banaschewski Banaschewski, Barker Barker, Bokde Bokde, Brühl Brühl, Desrivières Desrivières, Flor Flor, Garavan Garavan, Gowland Gowland, Grigis Grigis, Heinz Heinz, Martinot Martinot, Martinot Martinot, Artiges Artiges, Nees Nees, Orfanos Orfanos, Poustka Poustka, Smolka Smolka, Holz Holz, Vaidya Vaidya, Walter Walter, Whelan Whelan, Schumann Schumann, , , Howes Howes, Mehta Mehta, Pergola Pergola
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