Inflammation-induced depression. Studying the role of proinflammatory cytokines in anhedonia

Proinflammatory cytokines play a role in major depressive disorder. A core symptom of major depression is anhedonia, the inability to experience pleasure. Sensitivity of the reward system in the brain can be measured in the intracranial self-stimulation (ICSS) procedure in both mice and rats. In this thesis it is shown that peripheral activation of the immune system with lipopolysaccharide (LPS), leading to the rapid release of proinflammatory cytokines, and peripheral injection of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) significantly reduced responding for brain stimulation reward. Since this effect was independent of other LPS-induced sickness behaviors, such as decreased mobility and lower body weight due to loss of appetite, these results represent anhedonia. Furthermore it is shown that anhedonia persists longer than other symptoms of sickness behavior. The exact mechanism behind inflammation-induced anhedonia is still unknown. Since current antidepressants increase monoamine levels in the synaptic cleft it is conceivable that inflammation-induced anhedonia is accompanied by alterations in monoamine signaling in the brain. In vivo microdialysis studies were performed to measure extracellular levels of serotonin (5-HT), dopamine (DA) and their metabolites 5-HIAA, DOPAC and HVA. Microdialysis probes were placed in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), brain areas involved in the pathophysiology of major depressive disorder. After peripheral injection of LPS or TNF-α, extracellular levels of 5-HT did not change in both brain areas. Also DA levels were not altered in the NAc. In the mPFC, however, DA levels increased significantly after exposure to LPS. This demonstrates that anhedonia is not necessarily associated with decreased levels of 5-HT and DA in the synaptic cleft. Remarkably, metabolites of 5-HT and DA increased significantly after exposure to LPS and TNF-α. It appears that most 5-HIAA and DOPAC is formed after reuptake of released 5-HT and DA by serotonin transporters (SERT) and dopamine transporters (DAT), respectively. In the mPFC DAT expression is very low; therefore DA is taken up by norepinephrine transporters (NET) in this brain structure. Inhibition of SERT, DAT and NET activity by pretreatment with the triple reuptake inhibitor DOV 216,303, 30 minutes before exposure to LPS, blocked monoaminergic metabolite formation in the NAc and mPFC. These results suggest that LPS increases DAT activity in the NAc and SERT and NET activity in the mPFC, pointing to a role for increased monoamine transporter activity in inflammation-induced anhedonia. Indeed we demonstrate that LPS-induced anhedonia is absent in serotonin transporter knockout (SERT−/−) rats. Moreover, LPS-induced reductions in body weight were less severe in SERT−/− rats whereas LPS-induced increases in 5-HIAA were absent. LPS-induced increases in cytokines in SERT−/− rats, however, were unaltered compared to serotonin transporter wild type (SERT+/+) rats. Altogether, the results presented in this thesis indicate an important role for increased monoamine transporter activity, and especially increased SERT activity, in inflammation-induced anhedonia. However, it should be clear that more research is needed. Furthermore we stress that special attention should be given to the emotional status of patients with chronic inflammatory medical conditions and treat the psychic condition whenever necessary.