Abstract
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.
Highlights
Novel approaches to understanding the neural circuitry of behavior have revealed that dopamine neurons play a pivotal role in multiple depressive symptoms (Tye et al, 2013)
Methods: 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
In regard to potential effects of IFN-alpha on vesicular packaging and release, newly synthesized dopamine that is not packaged into synaptic vesicles is broken down into dihydroxyphenylacetic acid (DOPAC) in the extravesicular space by monoamine oxidase (Caudle et al, 2007)
Summary
Novel approaches to understanding the neural circuitry of behavior (ie, optogenetics) have revealed that dopamine neurons play a pivotal role in multiple depressive symptoms (Tye et al, 2013). Inflammatory cytokines and other biomarkers of inflammation are reliably elevated in a significant proportion of depressed patients, and peripheral administration of inflammatory cytokines, including interferon (IFN)-alpha, is well known to induce depressive-like behavior in both humans and nonhuman primates (Capuron et al, 2012; Felger and Miller, 2012). Chronic administration of IFN-alpha to patients with hepatitis C or malignant melanoma produces clinically significant depressive symptoms in up to 50% of treated patients that prominently features reduced motivation and psychomotor slowing (Felger and Miller, 2012), which are difficult to treat with standard antidepressant therapies and are often associated with dopamine depletion (Dunlop and Nemeroff, 2007). 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. 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.
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