Systemic tumor necrosis factor-alpha decreases brain stimulation reward and increases metabolites of serotonin and dopamine in the nucleus accumbens of mice

Behav Brain Res. 2013 Sep 15:253:191-5. doi: 10.1016/j.bbr.2013.07.038. Epub 2013 Jul 26.


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.

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.

MeSH terms

  • 3,4-Dihydroxyphenylacetic Acid / metabolism
  • Affect / drug effects
  • Animals
  • Body Weight / drug effects
  • Brain / physiology*
  • Dopamine / metabolism*
  • Electric Stimulation
  • Homovanillic Acid / metabolism
  • Hydroxyindoleacetic Acid / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microdialysis
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism*
  • Recombinant Proteins / metabolism
  • Reward*
  • Serotonin / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology*


  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • 3,4-Dihydroxyphenylacetic Acid
  • Serotonin
  • Hydroxyindoleacetic Acid
  • Dopamine
  • Homovanillic Acid