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

Archives of general psychiatry (Impact Factor: 14.48). 10/2012; 69(10):1044-53. DOI: 10.1001/archgenpsychiatry.2011.2094
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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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    • "Interestingly, both studies found no relationship between circulating inflammatory markers and TSPO binding suggesting that circulating inflammatory markers may not reflect central processes and to some extent, may be independent of microglial processes. Our findings add to a handful of other studies that have demonstrated an association between systemic inflammation and molecular substrates of behaviour, in particular the dopaminergic system in primates and humans (Capuron et al., 2012; Felger et al., 2013). "
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    ABSTRACT: Preclinical studies demonstrate that pro-inflammatory cytokines increase serotonin transporter availability and function, leading to depressive symptoms in rodent models. Herein we investigate associations between circulating inflammatory markers and brainstem serotonin transporter (5-HTT) availability in humans. We hypothesised that higher circulating inflammatory cytokine concentrations, particularly of tumour necrosis factor (TNF-α), would be associated with greater 5-HTT availability, and that TNF-α inhibition with etanercept (sTNFR:Fc) would in turn reduce 5-HTT availability. In 13 neurologically healthy adult women, plasma TNF-α correlated significantly with 5-HTT availability (rho=0.6; p=0.03) determined by [(123)I]-beta-CIT SPECT scanning. This association was replicated in an independent sample of 12 patients with psoriasis/psoriatic arthritis (rho=0.76; p=0.003). Indirect effects analysis, showed that there was a significant overlap in the variance explained by 5-HTT availability and TNF-α concentrations on BDI scores. Treatment with etanercept for 6-8weeks was associated with a significant reduction in 5-HTT availability (Z=2.09; p=0.03; r=0.6) consistent with a functional link. Our findings confirm an association between TNF-α and 5-HTT in both the basal physiological and pathological condition. Modulation of both TNF-α and 5-HTT by etanercept indicate the presence of a mechanistic pathway whereby circulating inflammatory cytokines are related to central nervous system substrates underlying major depression. Copyright © 2015. Published by Elsevier Inc.
    Brain Behavior and Immunity 08/2015; DOI:10.1016/j.bbi.2015.08.005 · 5.89 Impact Factor
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    • "= after controlling for sex and batch. Abbreviations: MDDmajor depressive disorder; BMIbody mass index; HAM-D 24Hamilton depression rating scale (24 item version); MADRSmontgomeryasberg depression rating scale; SHAPSsnaith hamilton pleasure scale; NAccnucleus accumbens; hs-CRPhigh-sensitivity c-reactive protein; TRPtryptophan; Kynkynurenine; KynAkynurenic acid; 3HK3-hydroxykynurenine; QAquinolinic acid; Kyn/TRPratio of kynurenine to tryptophan; KynA/3HKratio of kynurenic acid to 3-hydroxykynurenine; KynA/QAratio of kynurenic acid to quinolinic acid. in striatal volume in MDD (Kempton et al., 2011), and reports of interferon ␣-induced changes in glutamatergic neurotransmission in the striatum that correlated with motivation and fatigue (Capuron et al., 2007; Haroon et al., 2014), as well as interferon ␣ and endotoxin-induced decreases in the hemodynamic response to rewarding stimuli in the ventral striatum (Capuron et al., 2012; Eisenberger et al., 2010). "
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    ABSTRACT: Inflammation, which may be present in a subgroup of individuals with major depressive disorder (MDD), activates the kynurenine metabolic pathway to produce kynurenine metabolites kynurenic acid (KynA) and quinolinic acid (QA). We have previously reported an association between the ratio of KynA to QA and hippocampal volume in MDD. In animals, inflammation leads to deficits in incentive motivation. Given the central role of the nucleus accumbens (NAcc) and other regions of the striatum in motivated behavior, reward processing, and anhedonia, we hypothesized that abnormalities in the concentrations of kynurenine pathway metabolites would be associated with striatal volumes. As previously reported, after controlling for relevant confounds, the KynA/QA ratio was reduced in the serum of unmedicated patients with MDD (n=53) versus healthy controls (HC, n=47) and there was a non-significant trend in the correlation between KynA/QA and severity of anhedonia (r=-0.27, p<0.1). There was no significant difference between the MDD and HC groups in any of the individual kynurenine metabolites or volume of the striatum defined as the sum of the volumes of the NAcc, caudate, and putamen. After regressing out the effects of sex, analysis batch, and supratentorial volume, the kynurenine concentration and the ratio of kynurenine to tryptophan were inversely associated with striatal volumes in the MDD sample (p<0.05, uncorrected). Further, striatal volume was correlated with the items, "concentration difficulties", "lassitude", and "pessimism" from the Montgomery-Asberg Depression Rating Scale. Our results raise the possibility that activation of the kynurenine pathway is a marker of an inflammatory process that leads to reductions in striatal volume. However, unlike the hippocampus, the association does not appear to be mediated by the relative balance between KynA and QA. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Psychoneuroendocrinology 07/2015; 62:54-58. DOI:10.1016/j.psyneuen.2015.07.609 · 4.94 Impact Factor
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    • "Of note, the phenylalanine to tyrosine ratio significantly correlated with IFN-alpha–induced depressive symptoms (Felger et al., 2013a). Moreover, dietary depletion of dopamine precursors including phenylalanine and tyrosine has been found to decrease neural activation of the ventral striatum to hedonic reward (Bjork et al., 2014), similar to that observed following administration of IFNalpha or endotoxin (Eisenberger et al., 2010; Capuron et al., 2012). Together, these findings suggest that pharmacologic strategies that boost key components of dopamine synthesis may be efficacious, whereas dopamine reuptake inhibitors may be less effective, in treating depressive symptoms in patients with increased inflammation. "
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    ABSTRACT: Studies using neuroimaging and in vivo microdialysis in humans and nonhuman primates indicate that inflammatory cytokines such as interferon-alpha reduce dopamine release in the ventral striatum in association with depressive symptoms including anhedonia and psychomotor slowing. Herein, we examined whether reduced striatal dopamine release in rhesus monkeys chronically treated with interferon-alpha can be restored by administration of the dopamine precursor levodopa via reverse in vivo microdialysis. Levodopa completely reversed interferon-alpha-induced reductions in striatal dopamine release. No changes were found in the 3,4-dihydroxyphenylacetic acid to dopamine ratio, which increases when unpackaged dopamine is metabolized via monoamine oxidase. These findings suggest that inflammatory cytokines reduce the availability of dopamine precursors without affecting end-product synthesis or vesicular packaging and/or release and provide the foundation for future studies investigating therapeutic strategies that facilitate availability of dopamine precursors to improve depressive symptoms in patient populations with increased inflammation. © The Author 2015. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 01/2015; 18(4). DOI:10.1093/ijnp/pyu084 · 4.01 Impact Factor
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