Morphine and nicotine intake in high drinking in the dark mice is reduced by informatics-nominated and translationally relevant compounds

Introduction Recent studies have identified an important role for neuroinflammatory signaling in alcohol and substance use. Dysregulation of neuroimmune signaling has been shown to be involved in the risk for drinking to intoxication, and pharmacologically targeting immune pathways can reduce early-stage and chronic binge-like alcohol drinking. High drinking in the dark (HDID) mice also consume other drugs of abuse, such as morphine and nicotine. Thus, this study aimed to explore anti-inflammatory compounds to reduce morphine and nicotine intake in a genetic mouse model for substance use disorder. Methods We tested whether male and female inbred HDID mice will consume pharmacologically relevant levels of morphine and nicotine using the limited-access drinking in the dark assay (n = 7–12/sex/line). Drug intake was correlated with blood levels of morphine and nicotine metabolites (morphine-3-glucuronide and cotinine, respectively). We next tested whether the anti-inflammatory compounds terreic acid, pergolide, and apremilast would reduce morphine or nicotine intake (n = 11–14/sex/line/drug). Results Both inbred HDID (iHDID)-1 and iHDID-2 mouse lines drank pharmacologically relevant amounts of morphine and nicotine, where we observed a significant positive correlation between morphine and morphine-3-glucuronide in iHDID-2 male mice ( p = 0.04) and a significant positive correlation between nicotine and cotinine in iHDID-2 female mice ( p = 0.006). Terreic acid, pergolide, and apremilast significantly reduced morphine and nicotine intake in both lines and sexes. Discussion These findings highlight the versatility of iHDID-1 and iHDID-2 mice for both the consumption of drugs of abuse and as a model to test potential therapeutics to reduce drug intake. The results here provide further evidence that targeting inflammatory signaling offers promise for reducing opioid and nicotine use.