Interleukin 13 signaling modulates dopaminergic functions and nicotine reward in rodents

Neuroimmune signals can regulate neuronal function and affect behavior through mechanisms that are not yet fully understood. Here we investigated the action of interleukin 13 (IL-13), a cytokine that can be produced in the brain by both microglia and neurons. We show that dopamine-containing neurons in the ventral tegmental area (VTA) predominantly express the IL-13 receptor alpha 1 (IL-13Rα1) and exhibit presynaptic vesicular localization of neuronal IL-13. Exogenous application of IL-13, or its endogenous mobilization by optogenetics, reduced the activity of VTA dopaminergic neurons and opposed the stimulatory effects of nicotine on these neurons in rodents. These actions required IL-13Rα1, activation of the PI3K/AKT pathway, and functional hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Consistently, local infusion of IL-13 into the VTA markedly reduced nicotine self-administration in rodents. Collectively, these findings demonstrate that IL-13 acts in a neuromodulator-like fashion on mesolimbic dopamine neurons expressing IL-13Rα1. Our data also indicate that IL-13Rα1 signaling regulates the stimulatory actions of nicotine, suggesting a potential role for this neuronal immune signaling in reward processing and the addictive properties of nicotine.