Inflammation and metabolic dysfunction underly anhedonia-like behavior in antidepressant resistant male rats

Inflammation and metabolic dysfunction impair dopamine neurotransmission, which is thought to serve as a critical mechanism underpinning motivational deficits such as anhedonia across a range of psychiatric and neurological disorders. This difficult-to-treat transdiagnostic symptom has important implications for treatment resistant depression (TRD), and may warrant more targeted therapeutic approaches that address the underlying pathophysiological mechanisms. Using the adrenocorticotrophic hormone (ACTH) model of antidepressant treatment resistance we characterized the relationship between antidepressant-like and anhedonia-like behavioral responses to bupropion, mesocortical tyrosine hydroxylase (TH) expression, chronic low-grade inflammation, and metabolic changes in male rats. We demonstrate that chronic ACTH elicited both an antidepressant resistant- and anhedonia-like phenotype in forced swim and effort-related choice behavioral tasks, respectively. This was associated with decreased TH expression in the brain, increased central and peripheral markers of inflammation, and peripheral metabolic disturbances, including impairment of immune cell insulin action. Multivariate analysis revealed that peripheral interleukin-6 (IL-6) levels, immune cell glucose uptake and disturbance of nucleotide metabolism were strongly associated with anhedonia-like behavior. Post-hoc analyses further confirmed strong correlations between TH expression, inflammation and behavioral performance. These data suggest that stress hormone-induced upregulation of inflammation concurrent with the impairment of insulin-mediated glucose uptake into immune cells is associated with disruption of nucleotide metabolism, and potential impaired central dopamine synthesis contributing to the behavioral expression of anhedonia. These results suggest that immunometabolic perturbations concomitant with impaired insulin action at the level of the immune cell result in a metabolically deficient state that directly impacts nucleotide precursors essential for dopamine synthesis and effortful behavior. These results highlight the potential for immune and metabolic markers for individualized treatment of refractory depression and anhedonia.