With the rise in fast-food culture and the continued high numbers of tobacco-related deaths, there has been a great deal of interest in understanding the relationship between high-fat diet (HFD) and nicotine use behaviors. Using adult mice and a patch-clamp electrophysiology assay, we investigated the influence of HFD on the excitability of ventral tegmental area (VTA) dopamine neurons and pyramidal neurons in the medial prefrontal cortex (mPFC) given their role in modulating the reinforcing effects of nicotine and natural rewards. We then examined whether HFD-induced changes in peripheral markers were associated with nicotine use behaviors. Here, mice were assigned standard diet (SD) or HFD for 6 weeks and then trained to self-administer nicotine using an e-vape® self-administration (EVSA) assay. After the last session, changes in glucose, insulin, and leptin were assessed with ELISA. HFD-assigned mice displayed a decrease in intrinsic excitability of VTA dopamine neurons
but an increase in intrinsic excitability of layer VI prelimbic mPFC neurons. SD-assigned female mice demonstrated enhanced nicotine EVSA during fixed-ratio 3 relative to SD males. HFD-assigned male and female mice displayed increased nicotine EVSA during FR1. However, only HFD-assigned male mice exhibited enhanced nicotine EVSA during FR3. Finally, HFD-assigned male and female mice displayed increased leptin levels. However, we only observed a direct correlation between leptin levels and EVSA responding during FR1 in HFD-fed male mice. These results suggest that high-fat diet alter nicotine intake in a sex-specific manner, and this may be due to diet-induced changes in neuronal excitability and circulating leptin levels.