Dopaminergic Mechanisms of Reduced Basal Ganglia Responses to Hedonic Reward during Interferon-alpha Administration

Context: Previous studies have shown that inflammatory cytokines or cytokine inducers can alter basal ganglia activity including reduced responsiveness to rewarding stimuli that may be mediated by cytokine effects on dopamine function.Objective: To determine whether chronic administration of the inflammatory cytokine interferon (IFN)-alpha reduces the basal ganglia response to reward and whether such changes are associated with decreased presynaptic striatal dopamine function and altered behavior.Design: One cross-sectional and one longitudinal study.Setting: Outpatient research unit and neuroimaging facilities at Emory University.Participants: Medically stable, adult male and female patients with chronic hepatitis C virus (HCV) infection, eligible for IFN-alpha treatment.Main Outcome Measures: Neural activity in the ventral striatum during a hedonic reward task as measured by functional magnetic resonance imaging (fMRI). Uptake and turnover of radiolabeled [18F]DOPA in caudate and putamen using positron emission tomography. IFN-alpha-induced depression, anhedonia, fatigue and neurotoxicity.Results: HCV patients receiving IFN-alpha for 4-6 weeks (n=14) exhibited significantly reduced bilateral activation of the ventral striatum in the win versus lose condition of a gambling task compared to HCV patients awaiting IFN-alpha treatment (n=14). Reduced activation of ventral striatum was in turn significantly correlated with anhedonia, depression and fatigue. In a separate longitudinal study, HCV patients treated with IFN-alpha for 4-6 weeks (n=12) exhibited significantly increased [18F]DOPA uptake and decreased [18F]DOPA turnover in caudate and putamen as well as in the same ventral striatal regions identified in the fMRI study. Baseline and percent change in [18F]DOPA uptake and turnover were correlated with behavioral alterations during IFN-alpha administration including depression, fatigue and neurotoxicity.Conclusions. These data replicate and extend findings that inflammatory stimuli including inflammatory cytokines such as IFN-alpha alter basal ganglia activity and reduce hedonic reward in association with significant changes in presynaptic striatal dopamine function consistent with decreased dopamine synthesis and/or release.