Dopaminergic Mechanisms of Reduced Basal Ganglia Responses to Hedonic Reward During Interferon Alfa Administration

Reduced activation of the ventral striatum is significantly correlated with greater symptoms of anhedonia, depression, and fatigue.

“Reduced activation of the ventral striatum, in turn, was significantly correlated with greater symptoms of anhedonia, depression, and fatigue”

Capuron and colleagues found decreased blood-oxygen level dependent responses in the ventral striatal regions during a hedonic gambling reward task in patients with HCV treated with IFN-α.

“Similarly, Capuron and colleagues examined PET changes in patients with HCV treated with IFN-α and found decreased blood-oxygen level dependent responses in the ventral striatal regions during a hedonic gambling reward task.”

Reduced activity in the ventral striatum was interrelated with reduced motivation, fatigue, and depressed mood on the neurotoxicity scale.

“Reduced activity in the ventral striatum was interrelated with reduced motivation, fatigue, and depressed mood on the neurotoxicity scale (140).”

Cytokines decrease dopamine release in the basal ganglia, associated with decreased effort-based motivation and reduced activation of reward circuitry in the ventral striatum.

“Dopamine has a fundamental role in motivation and motor activity, and cytokines have been shown to decrease the release of dopamine in the basal ganglia in association with decreased effort-based motivation as well as reduced activation of reward circuitry in the basal ganglia, in particular the ventral striatum89–91.”

Inflammatory stimuli are associated with reductions in reward responsiveness in the striatum across multiple neuroimaging platforms in otherwise non-depressed individuals given IFNα, endotoxin or typhoid vaccination.

“Inflammatory stimuli have been associated with reductions in reward responsiveness in the striatum across many neuroimaging platforms, demonstrating the validity and reproducibility of these cytokine-mediated effects on the brain in otherwise non-depressed individuals peripherally administered IFNα, endotoxin or typhoid vaccination and imaged by PET, functional magnetic resonance imaging (fMRI), M”

Long-term administration of IFNα is associated with reduced neural responses to a hedonic reward task in the bilateral ventral striatum.

“long-term administration of IFNα is associated with reduced neural responses to a hedonic reward task in the bilateral ventral striatum”

In hepatitis C patients receiving IFN-α for 4-6 weeks, PET with 18F-dopa showed increased uptake and decreased turnover of 18F-dopa in the same ventral striatal regions affected by IFN-α in the fMRI study.

“Patients exhibited increased uptake and decreased turnover of 18F-dopa in the same ventral striatal regions shown to be effected by IFN-α in the previously mentioned fMRI study (Capuron et al., 2012).”

Reduced ventral striatal activation was significantly associated with more severe symptoms of anhedonia, depressed mood, and fatigue.

“Reduced ventral striatal activation was in turn significantly associated with more severe symptoms of anhedonia, depressed mood, and fatigue (Capuron et al., 2012).”

These changes may occur through proinflammatory cytokine effects on dopaminergic functioning in the ventral striatum.

“These changes may occur through the effect of proinflammatory cytokines on dopaminergic functioning in the ventral striatum (Capuron et al., 2012), as outlined in section 1.2.”

After 4-6 weeks of IFN-α therapy, hepatitis C patients showed significantly attenuated ventral striatal activity to receipt of monetary rewards in a gambling task compared with hepatitis C patients not receiving IFN-α.

“For example, after 4–6 weeks of IFN-α therapy, patients with hepatitis C showed significantly attenuated ventral striatal activity (as measured by fMRI) to receipt of monetary rewards in a gambling task when compared with hepatitis C patients not receiving IFN-α (Capuron et al., 2012).”

Baseline and percent change in FDOPA uptake and turnover correlated with IFN-alpha-induced depression and fatigue scores.

“Baseline and percent change in FDOPA uptake and turnover were, in turn, correlated with IFN-alpha-induced depression and fatigue scores.”

In IFN-alpha-treated HCV+ subjects, FDOPA PET showed increased uptake and decreased turnover in the caudate, putamen, and ventral striatum.

“Interestingly, both increased uptake and decreased turnover of FDOPA in the caudate, putamen and ventral striatum of IFN-alpha-treated patients was found (Capuron et al., 2012).”

fMRI demonstrated decreased neural activation to a hedonic reward task during IFN-alpha administration that correlated with reduced motivation.

“Functional magnetic resonance imaging (fMRI) has also demonstrated decreased neural activation to a hedonic reward task during IFN-alpha administration that correlated with reduced motivation (Capuron et al., 2012).”

Pro-inflammatory cytokines can affect the release of neurotransmitters.

“Moreover, pro-inflammatory cytokines can affect the release of neurotransmitters (93).”