In the striatum, BP at baseline was significantly greater than BP post MP in both the MP+PBO condition (P<0.0005) and in MP+LPS condition (P<0.0005; Supplementary Figure 1). ΔBP due to MP+PBO was comparable to that found in other studies using similar MP doses and routes of administration.29, 30 The effects we observed (either due to MP+PBO or MP+LPS) were consistently greater than the calculated test–retest variability in baseline BP in our data (5.2%) as well as in other studies.27, 31

Post-MP scans were initiated 90 min after LPS administration and image acquisition continued for 120 min, a time period during which the peak effects of LPS on blood cytokine levels,12, 15, 16 neuronal function (glucose metabolism in 18F-FDG PET14 or BOLD signal in fMRI11, 46) and behavioral effects (fatigue and other sickness symptoms) occur.12, 15, 16, 21, 47 Plasma analyses confirmed that cytokines were elevated as anticipated post LPS administration in a manner consistent with prior studies (Figure 2).12, 15, 16

Four subjects underwent the LPS pre-treatment session before the PBO pre-treatment session and four subjects received pre-treatment sessions in the opposite order. No significant difference in ΔBP MP+LPS was observed between subjects whether LPS was given first or PBO was given first. The same result was found in ΔBP MP+PBO .

In previous studies, LPS administration produced a clear effect on fatigue;15, 16 however, in this study we did not observe fatigue when LPS was co-administered with MP. We speculate that MP partially counteracts LPS-induced behavioral effects through a central (brain) mechanism, rather than a peripheral mechanism, as MP had no effect on circulating levels of cytokines (r<0.4; P>0.3). This decoupling of LPS-induced behavioral effects (fatigue and other sickness symptoms) and immune effects (blood cytokine levels) in the presence of MP is a novel result which indicates that blood cytokine concentrations may not be reliable indicators of the effects of systemic inflammation on brain-related symptoms. The potential effect of elevated cytokines in blood on the brain will depend on the susceptibility of the brain to these influences. In this study, it appears that MP had an effect on the brain that prevented the typical feeling of fatigue induced by LPS. Since both LPS alone and MP alone produce similar increases in DA, our data suggest that striatal DA levels do not have a direct relationship with fatigue. It is possible that DA in other brain regions is implicated in fatigue, or that other effects of MP counteracted fatigue (for example, the inhibition of norepinephrine uptake).48

Prior studies have suggested a cross sensitization between stressors and DA changes.49, 50 But, there appear to be differences between the effects of short- and long-term neuroimmune activation. In rodents, LPS induced an increase in DA concentration, an effect which peaked 2 h after LPS administration.24 Mice acutely pre-treated with LPS and cocaine displayed greater locomotion in a behavioral task compared to pre-treatment with cocaine alone.51 In nonhuman primates, 2 weeks of IFNα (a cytokine involved in inflammatory signaling) caused an increase in amphetamine-stimulated DA release over amphetamine alone.25 Our findings are consistent with prior studies, namely, stimulated DA elevation was enhanced with an acute dose of LPS compared to placebo. Studies of chronic inflammation have not found a synergistic effect of inflammation on DA activity. Capuron et al.52 found reduced 18F-DOPA uptake in humans after chronic IFNα administration. Chronic treatment with IFNα was also observed to reduce striatal dopamine release in primates as measured by microdialysis.26 In fact, the same monkeys studied by Felger et al.25 that experienced cytokine-enhanced DA release after 2 weeks showed a reversal of this effect when IFNα administration was extended to 4 weeks.

Imaging studies in humans have demonstrated a link between neuroinflammation and activity in the striatum. However, there appear to be differences in the effects on the ventral versus dorsal striatum. Using fMRI, Felger et al.20 showed a decrease in ventral striatal connectivity (during resting state) in depressed individuals with neuroinflammation. In non-depressed populations, ventral striatal BOLD activity in response to reward was blunted by both an acute dose of LPS12, 13 and chronic IFNα administration.52 The findings of these fMRI studies were localized to ventral striatum and indicate a reduction in reward reactivity during immune activation. In contrast, the present study found a synergistic effect of immune activity on DA elevation only in the dorsal striatum (caudate and putamen). DA in the dorsal (as opposed to ventral) striatum has been linked to response inhibition, another important behavioral characteristic of substance abuse.53, 54, 55 Low DA receptor availability in the dorsal striatum (as measured by PET imaging in humans) has been associated with impaired response inhibition.56, 57, 58, 59 The results of the present study are consistent with this body of work and represent a novel contribution to it, namely, that DA activity in response to a stressor is enhanced in the dorsal striatum.

The interaction between an immune response and DA signaling may carry unappreciated risks. If in the presence of inflammation, a dopaminergic medication or other stimulus with addiction potential produces higher DA elevation in the dorsal striatum than without, then it is reasonable to expect that the addiction liability of the stimulus may be increased through impaired response inhibition. Consider an individual experimenting with illicit stimulants or an adolescent prescribed Ritalin (MP), either of whom are experiencing short-term neuroinflammation. Both could be at increased risk for addiction due to reduced inhibitory control caused by a supraphysiologic DA elevation. We believe our findings call for further investigation of patient populations who may be suffering from neuroinflammation and are using or abusing stimulants.