Leptin Promotes Striatal Dopamine Release via Cholinergic Interneurons and Regionally Distinct Signaling Pathways

Dopamine (DA) is a critical regulator of striatal network activity and is essential for motor activation and reward-associated behaviors. Previous work has shown that DA is influenced by the reward value of food, as well as by hormonal factors that reguate food intake and energy expenditure. Changes in striatal DA signaling also have been linked to aberrant eating pat-terns. Here we test the effect of leptin, an adipocyte-derived hormone involved in feeding and energy homeostasis regulation, on striatal DA release and uptake. Immunohistochemical evaluation identified leptin receptor (LepR) expression throughout mouse striatum, including on striatal cholinergic interneurons (ChIs) and their extensive processes. Using fast-scan cyclic vol-tammetry (FSCV), we found that leptin causes a concentration-dependent increase in evoked extra-cellular DA concentration ([DA](o)) in dorsal striatum (dStr) and nucleus accumbens (NAc) core and shell in male mouse striatal slices, and also an increase in the rate of DA uptake. Further, we found that leptin increases ChI excitability, and that the enhancing effect of leptin on evoked [DA]o is lost when nicotinic acetylcholine (ACh) receptors are antagonized or when examined in striatal slices from mice lacking ACh synthesis. Evaluation of signaling pathways underlying leptin's action revealed a requirement for intracellular Ca2+, and the involvement of different downstream pathways in dStr and NAc core versus NAc shell. These results provide the first evidence for dynamic regulation of DA release and uptake by leptin within brain motor and reward pathways, and highlight the involvement of ChIs in this process.

Automated summary

This study found that leptin regulates dopamine release and uptake in the striatum, affecting motor and reward pathways. The results suggest that leptin increases dopamine release by modulating the excitability of cholinergic interneurons through nicotinic acetylcholine receptors. This highlights the important neuroregulatory role of leptin in the brain.