title: 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 D2antagonist 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 in11C-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.
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT, USA.|Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Petrulli
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA.
authors.forename: B
authors.initials: B
authors.lastname: Kalish
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA.
authors.forename: N B
authors.initials: NB
authors.lastname: Nabulsi
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Denali Therapeutics Inc., South San Francisco, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Hannestad
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT, USA.|Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA.|Department of Psychiatry, Yale University, New Haven, CT, USA.
authors.forename: E D
authors.initials: ED
authors.lastname: Morris
mesh_terms: D000328:Adult; D002250:Carbon Radioisotopes; D016022:Case-Control Studies; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology*; D015850:Interleukin-6 / Q000276:immunology; D016209:Interleukin-8 / Q000187:drug effects / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology*; D017072:Neostriatum / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D049268:Positron-Emission Tomography; D020891:Raclopride; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000276:immunology; D055815:Young Adult
chemical_list: C508606:CXCL8 protein, human; D002250:Carbon Radioisotopes; D000697:Central Nervous System Stimulants; C581293:DRD2 protein, human; D018492:Dopamine Antagonists; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D008774:Methylphenidate; D020891:Raclopride; D004298:Dopamine