Morphine Exposure Reduces Nicotine-Induced Upregulation of Nicotinic Receptors and Decreases Volitional Nicotine Intake in a Mouse Model

INTRODUCTION: Nicotine addiction remains a primary health concern as tobacco smoking remains the number one cause of preventable death in America. At the same time, America is still facing the threat of the opioid epidemic. While the prevalence of smoking combustible cigarettes or electronic nicotine delivery systems in the United States varies between 12% and 35%, the smoking rates among the opioid use dependent (OUD) population is 74%–97%. We examined changes in brain reward mechanisms in which co-use of nicotine and opioids may result in enhanced reward and reinforcement. AIMS AND METHODS: Adult male and female α4-mCherryα6-GFP mice (C57BL/6J) were used in conditioned place preference (CPP) and microscopy assays to examine reward-related behavior and nicotinic acetylcholine receptor (nAChR) upregulation following treatments with saline, nicotine, morphine, or nicotine plus morphine. Following this, separate mice were trained in e-Vape self-administration assays to examine morphine’s impact on nicotine reinforcement. RESULTS: We observed that nicotine and morphine coexposure in a CPP assay did not produce enhanced reward-related behavior when compared with nicotine or morphine alone. In parallel we observed coexposure reduced nicotine-induced upregulation of nAChRs on ventral tegmental area dopamine and GABA neurons. Additionally, we observed that concurrent morphine exposure reduced nicotine (plus menthol) vapor self-administration in male and female mice. CONCLUSIONS: While nicotine use is high among OUD individuals, our CPP assays suggest coexposure not only fails to enhance reward-related behavior but also reduces nicotine-induced changes in ventral tegmental area neurobiology. Our self-administration assays suggest that morphine exposure during nicotine acquisition reduces nicotine reinforcement-related behavior. IMPLICATIONS: While some may postulate that the co-use of opioids and nicotine may be driven by reward-related mechanisms, our data indicate that opioid exposure may hinder nicotine intake due to reduced upregulation of nAChRs critical for nicotine reward and reinforcement. Thus, the high co-use in OUD individuals may be a result of other mechanisms and this warrants further investigations into nicotine and opioid co-use.