Nicotine Administration Robustly Enhances Fentanyl-Induced Dopamine Transmission Within the Dorsal Lateral Striatum

Opioid use disorder (OUD) is a prevalent public health concern in the United States. ∼70% of all drug overdose deaths are attributable to fentanyl, demonstrating a need to identify risk factors underlying the escalation of fentanyl use. Nicotine use is a risk factor associated with increased consumption of opioids across both clinical and preclinical populations. Our prior findings show that nicotine administration escalates consumption of opioids and that this elevated consumption persists despite adverse consequences in rodents, demonstrating a behavioral phenotype resembling those that emerge following protracted experience with opioids. Prolonged drug consumption is associated with a shift towards increased dopamine (DA) transmission within dorsal lateral striatum (DLS), a brain area critical for the development of inflexible behaviors. The present study sought to characterize the behavioral and neurochemical effects of nicotine on fentanyl administration. A dose-response curve was used to determine the effect of nicotine on fentanyl consumption as a function of dose in males and females. Systemic pretreatment with nicotine enhanced fentanyl intake across all doses relative to nicotine-naïve controls, suggesting that nicotine augments responding for opioids without evident effects on sensitivity to fentanyl. Additionally, fast-scan cyclic voltammetry (FSCV) was applied to measure DLS DA transmission in response to fentanyl administration and to quantify any effect of nicotine on this response in male rats. Fentanyl administration enhanced DA concentrations within DLS, and this effect was potentiated by nicotine pretreatment. These findings support that enhanced DA transmission in DLS may mechanistically contribute to nicotine-induced increases in the motivation for opioids. Significance statement Misuse of synthetic opioids such as fentanyl is primarily responsible for alarming rates of fatal overdose thus highlighting the need for studies designed to elucidate the mechanisms contributing to opioid misuse liability. Polysubstance use of opioids and nicotine-containing products is remarkably common and multiple clinical and preclinical observations support that nicotine markedly increases the consumption of opioids. Here, using fast-scan cyclic voltammetry in rodent models, we demonstrate that fentanyl administration robustly enhances dopamine concentrations within the dorsal lateral striatum, a brain area heavily implicated in multiple behavioral features of problematic drug use. Moreover, nicotine administration significantly potentiates this fentanyl-evoked dopamine concentration which may underlie the enhanced liability for opioid use disorders observed in users of nicotine-containing products.