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

Abstract

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]2β-carbomethoxy-3β-(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.

Circulating tumour necrosis factor is highly correlated with brainstem serotonin transporter availability in humans

“…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). Serotonergic systems interact highly with dopaminergic systems it is likely that these systems interact and there are a number of intermediate steps that link circulating TNF to brainstem 5-HTT availability.…”

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

“…These deficits in dopamine release were recovered by administration of the dopamine precursor L-DOPA via reverse microdialysis, indicating that dopamine synthesis was impaired, whereas vesicular packaging (by the vesicular monoamine transporter) and release were intact . Of note, decreased dopamine release during in vivo microdialysis was highly correlated with decreased effort-based consumption of sucrose pellets using a puzzle feeder (Felger et al, 2013b). No effects of IFN-α were found on consumption of sucrose pellets that were freely available in a feeding tray.…”

“…As described above, data in laboratory animals and humans indicate that dopamine is a primary target of the effects of inflammation on the brain. These findings have been manifested by alterations in dopamine metabolism following the administration of inflammatory stimuli as well as the presence of decreased effort-based motivation for reward (Kitagami et al, 2003;Felger et al, 2013bFelger et al, , 2015. In addition, increased peripheral CRP in patients with major depression has been associated with symptoms of anhedonia as well as psychomotor retardation that is mediated by inflammation-induced alterations in functional connectivity between ventral and dorsal striatum and ventromedial prefrontal cortex .…”

“…For example, using PET, administration of radiolabeled L-DOPA to humans treated with IFN-α was found to lead to increased L-DOPA uptake and decreased L-DOPA release consistent with dopamine depletion (Capuron et al, 2012). Decreased dopamine release was also demonstrated in IFN-α-treated rhesus monkeys that, like humans, exhibit a depressive-like huddling behavior after chronic IFN-α exposure (Felger et al, 2007(Felger et al, , 2013b. Indeed, after 4 weeks of IFN-α administration at doses similar to those given to humans for cancer treatment, rhesus monkeys exhibited decreased CSF dopamine metabolites (Felger et al, 2007).…”

“…Indeed, after 4 weeks of IFN-α administration at doses similar to those given to humans for cancer treatment, rhesus monkeys exhibited decreased CSF dopamine metabolites (Felger et al, 2007). Moreover, using in vivo microdialysis of basal ganglia nuclei, these laboratory animals demonstrated decreased extracellular dopamine release following administration (by reverse microdialysis) of potassium, which leads to a voltage-dependent dopamine release, as well as amphetamine, which stimulates dopamine release and blocks dopamine reuptake (Felger et al, 2013b). These deficits in dopamine release were recovered by administration of the dopamine precursor L-DOPA via reverse microdialysis, indicating that dopamine synthesis was impaired, whereas vesicular packaging (by the vesicular monoamine transporter) and release were intact .…”