Levodopa reverses cytokine-induced reductions in striatal dopamine release.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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)-α (20 MIU/m(2) 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 [(11)C]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 [(18)F]2ß-carbomethoxy-3ß-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane. Anhedonia-like 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 [(11)C]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.