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

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)-alpha (20 MIU/m(2) s.c.) or saline for 4 weeks. In vivo microdialysis was used to investigate IFN-alpha effects on DA release in the striatum. In addition, positron emission tomography (PET) with [C-11] raclopride was used to examine IFN-alpha-induced changes in DA2 receptor (D2R) binding potential before and after intravenous amphetamine administration. DA transporter binding was measured by PET using [F-18]2 beta-carbomethoxy-3 beta-(4-chlorophenyl)-8-(2-fluoroethyl) nortropane. Anhedonia-like behavior (sucrose consumption) was assessed during saline and IFN-alpha administration. In vivo microdialysis demonstrated decreased release of DA after 4 weeks of IFN-alpha administration compared with saline. PET neuroimaging also revealed decreased DA release after 4 weeks of IFN-alpha as evidenced by reduced displacement of [C-11] raclopride following amphetamine administration. In addition, 4 weeks of IFN-alpha was associated with decreased D2R binding but no change in the DA transporter. Sucrose consumption was reduced during IFN-alpha 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-alpha 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.