Pro-inflammatory cytokines induce anhedonia in mice and increase monoamine transporter activity in the nucleus accumbens

A growing body of evidence suggests that proinflammatory cytokines contribute to the pathogenesis of depression due to a general medical condition [1]. Lipopolysaccharide (LPS), a component of the outer membrane of gram-negative bacteria, binds to toll-like receptor 4 (TLR4) leading to the rapid release of pro-inflammatory cytokines. In rats these LPS-induced pro-inflammatory cytokines induce anhedonia, i.e. the inability to experience pleasure, a core symptom of major depressive disorder. This was shown by increased thresholds in an intracranial self-stimulation (ICSS) paradigm [2]. The underlying mechanisms are largely unknown. We hypothesize that peripheral cytokines reach the brain and affect central monoamine signalling via the enhancement of monoamine reuptake which leads to anhedonia. To demonstrate that peripheral cytokines induce anhedonia in mice, C57BL/6 mice were trained in the ICSS paradigm. After establishment of stable ICSS thresholds, mice were treated with saline or LPS (133 mg/kg, i.p.). Animals were tested in the ICSS paradigm 1 h, 4 h, 24 h, 48 h, 72 h and 96 h after administration. In another group of mice we measured extracellular monoamine (metabolite) concentrations in the nucleus accumbens (NAc). In the first microdialysis study, mice were treated with saline followed by a saline or LPS injection (133 mg/kg, i.p.) 30 min later. To test the involvement of monoamine transporters, in the second study, animals were injected with the triple reuptake inhibitor DOV 216,303 (5 mg/kg, i.p.) 30 minutes before the saline or LPS injection (133 mg/kg, i.p.). During the microdialysis studies 30-minute samples were collected during a period of 6.5 h. Results: In the ICSS study, repeated measures ANOVA with time as within factor and treatment as between-subjects factor revealed a significant time × treatment interaction and a significant effect of treatment (F(1.7,24.0) = 6.263, p = 0.009 and F(1,14) = 9.2, p = 0.009 respectively). One-way ANOVA per time point revealed significant elevations of ICSS thresholds in the LPS group at time points 1 h and 4 h after injection. Peripheral LPS injection did not affect serotonin and dopamine levels in the NAc. However, repeated measures ANOVA revealed significant time × treatment interactions and effects of treatment for the metabolites (5-HIAA: F(3.6,35.9) = 16.8, p0.05 and p>0.05 respectively and HVA: F(1.9,22.0) = 4.1 and p>0.05 respectively). Altogether, these results indicate that pro-inflammatory cytokines play a role in the communication between the immune system and central nervous system. The increased elevations in ICSS thresholds after exposure to LPS suggest that pro-inflammatory cytokines induce anhedonia. The microdialysis data suggest that monoamine transporters in the nucleus accumbens are involved in this process, since pre-exposure to the triple reuptake inhibitor DOV 216,303 reduced or even prevented the increased reuptake of monoamines by LPS, as reflected by the decreased extracellular levels of monoamine metabolites.