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.

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.