title: Systemic tumor necrosis factor-alpha decreases brain stimulation reward and increases metabolites of serotonin and dopamine in the nucleus accumbens of mice.
abstract: Many patients with chronic inflammatory disorders have an abnormal high prevalence of major depression accompanied by elevated levels of tumor necrosis factor-α (TNF-α). We hypothesize that systemic TNF-α increases brain monoamine metabolism, which might induce anhedonia (i.e. a core symptom of major depression). The effect of an intraperitoneal TNF-α injection on extracellular monoamine and metabolite concentrations was investigated by in vivo microdialysis in the nucleus accumbens (NAc) of C57BL/6 mice. In another group, the effects of TNF-α on body weight and intracranial self-stimulation (ICSS) thresholds were measured. TNF-α reduced body weight and increased ICSS thresholds, suggesting a state of anhedonia. TNF-α did not affect serotonin levels, but increased its metabolite 5-HIAA in the NAc. Remarkably, TNF-α also increased the dopamine metabolite HVA, without affecting dopamine levels itself. These data concur with earlier findings that pro-inflammatory cytokines enhance serotonin transporter activity, and possibly also dopamine transporter activity in the brain. However, more research is needed to understand the precise molecular mechanisms by which TNF-α increases transporter activity and anhedonia.
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands. F.vanHeesch@uu.nl
authors.forename: Floor
authors.initials: F
authors.lastname: van Heesch
authors.forename: Jolanda
authors.initials: J
authors.lastname: Prins
authors.forename: Gerdien A H
authors.initials: GA
authors.lastname: Korte-Bouws
authors.forename: Koen G C
authors.initials: KG
authors.lastname: Westphal
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lemstra
authors.forename: Berend
authors.initials: B
authors.lastname: Olivier
authors.forename: Aletta D
authors.initials: AD
authors.lastname: Kraneveld
authors.forename: S Mechiel
authors.initials: SM
authors.lastname: Korte
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000339:Affect / Q000187:drug effects; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism*; D004558:Electric Stimulation; D006719:Homovanillic Acid / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017551:Microdialysis; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012201:Reward; D012701:Serotonin / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D004298:Dopamine; D006719:Homovanillic Acid
keywords: 5-HIAA; 5-HT; 5-hydroxyindoleacetic acid; Anhedonia; DA; DAT; DOPAC; HVA; ICSS; Intracranial self-stimulation; LPS; MD; Microdialysis; NAc; Nucleus accumbens; Repeated measures ANOVA; SERT; SSRI; Serotonin transporter; TNF-α; VMAT-2; dihydroxyphenylacetic acid; dopamine; dopamine transporter; homovanillic acid; intracranial self-stimulation; lipopolysaccharide; major depression; nucleus accumbens; repeated measures analysis of variance; selective serotonin reuptake inhibitor; serotonin; serotonin transporter; tumor necrosis factor-α; vesicular monoamine transporter 2