Abstract
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-13R alpha 1) 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-13R alpha 1, 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-13R alpha 1. Our data also indicate that IL-13R alpha 1 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.