Chronic nicotine vapor-induced enhancement of ethanol drinking-in-the-dark is associated with reduced medial prefrontal cortical activity.

RATIONALE: Nicotine vaping is associated with increased alcohol use, including binge drinking, yet the neurobehavioral mechanisms underlying nicotine-alcohol interactions remain poorly understood due to limited translational preclinical models capturing intrapulmonary nicotine exposure effects on binge-like ethanol intake. OBJECTIVES: We establish a mouse model combining nicotine vapor exposure (NVE) with drinking-in-the-dark (DID) to examine effects on binge-like ethanol (EtOH) consumption and determine whether these effects are associated with medial prefrontal cortex (mPFC) activity and nicotinic acetylcholine receptor (nAChR) signaling. METHODS: Male and female mice were passively exposed to nicotine or vehicle vapor prior to 2-h and 4-h EtOH DID across repeated cycles. EtOH intake, blood ethanol concentrations (BECs), and control solution consumption were measured. Neuronal activation in prelimbic (PrL) and medial orbitofrontal cortex (mOFC) was assessed using c-Fos immunofluorescence. Mecamylamine was used to evaluate nAChR involvement. RESULTS: NVE produced physiologically relevant nicotine exposure and selectively increased EtOH consumption during 2-h and 4-h DID sessions without altering control solution intake. NVE also elevated BECs, which were positively correlated with EtOH consumption. Following DID, NVE was associated with reduced mPFC activity in PrL and mOFC; however, EtOH consumption was inversely correlated specifically with mOFC activity. nAChR blockade attenuated NVE-induced increases in EtOH consumption during 2-h DID only. CONCLUSIONS: Passive nicotine vapor exposure enhances binge-like EtOH intake and is associated with reduced mPFC engagement, particularly within mOFC, suggesting a mechanism underlying nicotine-alcohol interactions. These effects are partly mediated by nAChRs, identifying mPFC nAChRs as potential therapeutic targets for nicotine-alcohol polysubstance use.