Systemic inflammation enhances stimulant-induced striatal dopamine elevation

Abstract

Changes in the mesolimbic dopamine (DA) system are implicated in a range of neuropsychiatric conditions including addiction, depression and schizophrenia. Dysfunction of the neuroimmune system is often comorbid with such conditions and affects similar areas of the brain. The goal of this study was to use positron emission tomography with the dopamine D₂ antagonist tracer, ¹¹C-raclopride, to explore the effect of acute immune activation on striatal DA levels. DA transmission was modulated by an oral methylphenidate (MP) challenge in order to reliably elicit DA elevation. Elevation in DA concentration due to MP was estimated via change in ¹¹C-raclopride binding potential from the baseline scan. Prior to the post-MP scan, subjects were pre-treated with either the immune activator lipopolysaccharide (LPS) or placebo (PBO) in a cross-over design. Immune activation was confirmed by measuring tumor necrosis factor alpha (TNFα), interleukin (IL)-6 and IL-8 concentration in plasma. Eight healthy subjects were scanned four times each to determine the MP-induced DA elevation under both LPS and PBO pre-treatment conditions. MP-induced DA elevation in the striatum was significantly greater (P<0.01) after LPS pre-treatment compared to PBO pre-treatment. Seven of eight subjects responded similarly. This effect was observed in the caudate and putamen (P<0.02), but was not present in ventral striatum. DA elevation induced by MP was significantly greater when subjects were pre-treated with LPS compared to PBO. The amplification of stimulant-induced DA signaling in the presence of systemic inflammation may have important implications for our understanding of addiction and other diseases of DA dysfunction.

Figure 1

Schematic depiction of a session containing two ¹¹C-raclopride PET scans: baseline and post MP. Each subject underwent two of these sessions with different pre-treatments: LPS or placebo. The order of the sessions was randomized. Blood sampling and POMS questions were performed periodically (denoted by arrows) from the start of pre-treatment until the end of the post-MP scan. LPS, lipopolysaccharide; MP, methylphenidate; PET, positron emission tomography; PBO, placebo; POMS, Profile of Mood States.

Figure 2

Mean cytokine concentration of TNFα (▪), IL-6 (♦) and IL-8 (•) in MP+LPS scans (n=8). The corresponding mean POMS score of fatigue is plotted on a secondary axis (▴). Error bars are shown as the standard deviation between subjects. IL, interleukin; LPS, lipopolysaccharide; MP, methylphenidate; POMS, Profile of Mood States; TNFα, tumor necrosis factor alpha.

Figure 3

ΔBP values in striatum from each subject in each condition. Seven of eight subjects exhibited greater ΔBP after MP+LPS administration (gray) versus MP+PBO (white; P<0.01). Line segments were added to indicate the same subject in different conditions. Preliminary results (n=2) of ΔBP after LPS alone are plotted in black in the right-most column. These subjects did not receive any other scan condition. BP, binding potential; LPS, lipopolysaccharide; MP, methylphenidate; PBO, placebo.

Figure 4

Images created from SRTM modeling at the voxel level. Analyses were performed on images aligned to a common space and averaged: (a) mean ΔBP_MP+LPS image, (b) mean ΔBP_MP+PBO image and (c) significance image created by paired t-testing ΔBP between drug conditions at each voxel. Voxel intensity is calculated as (1.0−P-value). Voxel values are only displayed where (1.0−P-value)>0.90. In this two-tailed t-test, no voxels were found to be significant for ΔBP_MP+LPS<ΔBP_MP+PBO. The sparsity of significant differences on the left side of the brain is likely due to greater observed variability in the MP+PBO condition in left ROIs (see Table 1 for ROI level values). BP, binding potential; LPS, lipopolysaccharide; MP, methylphenidate; PBO, placebo; SRTM, simplified reference tissue model.