The role of IL-6 in dopamine dysregulation underlying anhedonia phenotype in rats

ABSTRACT Aims To investigate the role of peripheral metabolic change and chronic low-grade inflammation on striatal dopamine dynamics and anhedonia-like behaviour induced by hypothalamic–pituitary–adrenal (HPA) axis disruption. Methods Wistar rats were trained in a progressive-ratio/concurrent effort-related choice paradigm to assess effort-related decision making. After reaching a stable baseline, animals received daily injections of adrenocorticotrophic hormone (ACTH) or saline for 24 days. On the 23 rd and 24 th day, animals received a bupropion challenge (10mg/kg and 20mg/kg respectively) 30 minutes prior to the behavioural testing session. On the 25 th day, animals received a single injection of bupropion (20mg/kg) 30 minutes prior to euthanasia. Peripheral and central inflammatory markers were assessed through ELISA and In-Cell Western assay; glucose transport activity was assessed in peripheral blood mononuclear cells though a commercial assay kit; brain levels of dopaminergic and inflammatory markers were assessed in the nucleus accumbens (NAc) and prefrontal cortex (PFC) through immunohistochemistry; and serum central carbon metabolism metabolites were assessed through a metabolomics approach. Results ACTH induced an anhedonia-like phenotype, decreased tyrosine hydroxylase (TH) levels in the NAc, increased peripheral IL-6 levels, and decreased glucose transport activity and glucose metabolites when compared to control group. Bupropion treatment was not able to reverse the anhedonic phenotype. Glucose uptake was positively correlated to behaviour; TH levels were correlated to microglia volume; metabolites were correlated to TH levels; and IL6 was correlated to TH levels and metabolites. Conclusion Chronic ACTH treatment can induce treatment-resistant anhedonia in rats, and the interaction between peripheral immunometabolic state and central dopamine synthesis is a potential mechanism underlying this phenotype.