Chronic Interferon-α Decreases Dopamine 2 Receptor Binding and Striatal Dopamine Release in Association with Anhedonia-Like Behavior in Nonhuman Primates

1] Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA [2] The Winship Cancer Institute, Emory University, Atlanta, GA, USA.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.05). 05/2013; 38(11). DOI: 10.1038/npp.2013.115
Source: PubMed


Neuroimaging studies in humans have demonstrated that inflammatory cytokines target basal ganglia function and presynaptic dopamine (DA), leading to symptoms of depression. Cytokine-treated nonhuman primates also exhibit evidence of altered DA metabolism in association with depressive-like behaviors. To further examine cytokine effects on striatal DA function, eight rhesus monkeys (four male, four female) were administered interferon (IFN)-α (20 MIU/m2 s.c.) or saline for 4 weeks. In vivo microdialysis was used to investigate IFN-α effects on DA release in the striatum. In addition, positron emission tomography (PET) with [11C]raclopride was used to examine IFN-α-induced changes in DA2 receptor (D2R) binding potential before and after intravenous amphetamine administration. DA transporter binding was measured by PET using [18F]2β-carbomethoxy-3β-(4- chlorophenyl)-8-(2-fluoroethyl)nortropane. Anhedonialike behavior (sucrose consumption) was assessed during saline and IFN-α administration. In vivo microdialysis demonstrated decreased release of DA after 4 weeks of IFN-α administration compared with saline. PET neuroimaging also revealed decreased DA release after 4 weeks of IFN-α as evidenced by reduced displacement of [11C]raclopride following amphetamine administration. In addition, 4 weeks of IFN-α was associated with decreased D2R binding but no change in the DA transporter. Sucrose consumption was reduced during IFN-α administration and was correlated with decreased DA release at 4 weeks as measured by in vivo microdialysis. Taken together, these findings indicate that chronic peripheral IFN-α exposure reduces striatal DA release in association with anhedonia-like behavior in nonhuman primates. Future studies examining the mechanisms of cytokine effects on DA release and potential therapeutic strategies to reverse these changes are warranted. © 2013 American College of Neuropsychopharmacology. All rights reserved.

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Available from: Jennifer C Felger, Sep 22, 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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    • "However, 3 to 5 animals per group is common in nonhuman primate studies employing in vivo microdialysis techniques, and as with previous studies, a within-subject design was used to reduce effects of inter-subject variability and increase statistical power (Felger et al., 2013b). An additional limitation is that this study was designed to examine only whether the dopamine precursor L-DOPA could restore cytokine-induced reductions in dopamine release, which were previously found to correlate with decreases in effort-based sucrose consumption, a measure of anhedonia (Felger et al., 2013b). Future studies will be necessary to investigate whether restoration of dopamine release by agents that increase dopamine synthesis can reverse cytokine-related behavioral symptoms in humans or nonhuman primates. "
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