Dopaminergic mechanisms of reduced Basal Ganglia responses to hedonic reward during interferon alfa administration.

Archives of general psychiatry (Impact Factor: 13.75). 10/2012; 69(10):1044-53. DOI: 10.1001/archgenpsychiatry.2011.2094
Source: PubMed

ABSTRACT CONTEXT Inflammatory cytokines or cytokine inducers can alter basal ganglia activity, including reducing responsiveness to rewarding stimuli that may be mediated by cytokine effects on dopamine function. OBJECTIVES To determine whether long-term administration of the inflammatory cytokine interferon alfa reduces the basal ganglia response to reward and whether such changes are associated with decreased presynaptic striatal dopamine function and altered behavior. DESIGN Cross-sectional and longitudinal studies. SETTING Outpatient research unit and neuroimaging facilities at Emory University, Atlanta, Georgia. PATIENTS Medically stable adults with chronic hepatitis C virus (HCV) infection eligible for interferon alfa treatment. MAIN OUTCOME MEASURES Neural activity in the ventral striatum during a hedonic reward task as measured by functional magnetic resonance imaging, uptake and turnover of radiolabeled fluorodopa F 18 (18F-dopa) in caudate and putamen using positron emission tomography, and interferon alfa-induced depression, anhedonia, fatigue, and neurotoxicity. RESULTS Patients with HCV receiving interferon alfa for 4 to 6 weeks (n = 14) exhibited significantly reduced bilateral activation of the ventral striatum in the win vs lose condition of a gambling task compared with patients with HCV awaiting interferon alfa treatment (n = 14). Reduced activation of the ventral striatum was, in turn, significantly correlated with anhedonia, depression, and fatigue. In a separate longitudinal study, patients with HCV treated with interferon alfa for 4 to 6 weeks (n = 12) exhibited significantly increased 18F-dopa uptake and decreased 18F-dopa turnover in caudate and putamen and in the same ventral striatal regions identified in the functional magnetic resonance imaging study. Baseline and percentage change in 18F-dopa uptake and turnover were correlated with behavioral alterations, including depression, fatigue, and neurotoxicity, during interferon alfa administration. CONCLUSIONS These data replicate and extend findings that inflammatory stimuli, including inflammatory cytokines, such as interferon alfa, alter basal ganglia activity and behavior in association with significant changes in presynaptic striatal dopamine function consistent with decreased dopamine synthesis or release.

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Available from: Giuseppe Pagnoni, Feb 18, 2015
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    • "We therefore explored effects of aging on the glutamate response to IFN-alpha in patients with hepatitis C virus (HCV) and determined whether these effects were associated with alterations in inflammatory markers and behaviors previously shown to be altered in IFN-alpha-treated patients including tumor necrosis factor (TNF) and its soluble receptor sTNFR2, motivation, and motor activity (Capuron et al., 2012; Majer et al., 2008; Raison et al., 2010). "
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    • "In humans, experimental inflammatory challenges (vs. placebo) lead to reduced, rather than increased, VS to monetary reward (Capuron et al., 2012; Eisenberger et al., 2010). Similarly, healthy individuals who report higher anhedonic symptoms, a major symptom of inflammatory disorders such as depression (Miller et al., 2009), show reduced reward activity to a monetary reward task. "
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    • "Recent studies indicate that cytokines can interfere with DA storage by reducing expression of the type 2 monoamine transporter (VMAT2) and also can suppress DA synthesis by reducing the availability of the essential cofactor tetrahydrobiopterin (Felger and Miller 2012). Patients treated with pro-inflammatory cytokines develop psychomotor slowing and fatigue and show reduced activation of nucleus accumbens as measured by fMRI (Capuron et al. 2012). Moreover, reductions in the presence of the DA metabolite homovanillic acid in cerebrospinal fluid were correlated with the degree of fatigue in patients treated with IFN-α (Felger and Miller 2012). "
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