Dexamphetamine-induced striatal hyperdopaminergia attenuates reward-related neural activation: A¹¹C-PHNO PET-fMRI...

Ventral striatum (VS) and ventromedial prefrontal cortex (vmPFC) encode the value of stimulus and outcome phases in a context-dependent manner to support motivated behaviour. In psychosis, disrupted motivational coding has been hypothesised to contribute to negative symptoms via reduced sensitivity to goal-relevant information, potentially linked to elevated striatal dopamine. Direct causal evidence for this mechanism in humans remains limited.

Healthy volunteers (N=28) underwent two simultaneous [¹¹C]-PHNO PET-fMRI sessions (placebo; oral dexamphetamine 0.5 mg/kg, double-blind, randomised crossover). During scanning, participants performed a decision-making task requiring trial-by-trial use of contextual cues to discriminate reward-predictive (relevant) from non-predictive (irrelevant) stimulus features. fMRI quantified context-relevant value coding during reward anticipation and positive-negative outcome responses. PET quantified D2/3 agonist binding potential (BPND) and dexamphetamine-induced dopamine release (ΔBPND). Mixed-effects models related BOLD responses to between- and within-subject components of BPND.

Task performance was high with no behavioural drug effects. Under placebo, VS showed greater activation to context-relevant versus irrelevant value during anticipation. Dexamphetamine significantly attenuated this effect, driven by reduced VS responses to relevant cues without increased responses to irrelevant features. Dexamphetamine also reduced outcome-related responses in VS; non-significantly in vmPFC. Across sessions, higher between-subject [¹¹C]-PHNO BPND was associated with stronger VS reward coding during anticipation and outcome, whereas within-subject BPND deviations did not explain additional variance beyond drug condition.

These findings support a mechanism by which elevated dopamine may impair motivational coding by reducing amplification of goal-relevant information, with potential relevance to negative symptoms such as apathy and anhedonia.