Behavioral and neuronal extracellular vesicle biomarkers associated with nicotine's enhancement of the reinforcing strength of cocaine in female and male monkeys

While the majority of people with cocaine use disorders (CUD) also co-use tobacco/nicotine, most preclinical cocaine research does not include nicotine. The present study examined nicotine and cocaine co-use under several conditions of intravenous drug self-administration in monkeys, as well as potential peripheral biomarkers associated with co-use. In Experiment 1, male rhesus monkeys (N = 3) self-administered cocaine (0.001–0.1 mg/kg/injection) alone and with nicotine (0.01–0.03 mg/kg/injection) under a progressive-ratio schedule of reinforcement. When nicotine was added to cocaine, there was a significant leftward/upward shift in the number of injections received. In Experiment 2, socially housed female and male cynomolgus monkeys (N = 14) self-administered cocaine under a concurrent drug-vs-food choice schedule of reinforcement. Adding nicotine to the cocaine solution shifted the cocaine dose-response curves to the left, with more robust shifts noted in the female animals. There was no evidence of social rank differences. To assess reinforcing strength, delays were added to the presentation of drug; the co-use of nicotine and cocaine required significantly longer delays to decrease drug choice, compared with cocaine alone. Blood samples obtained post-session were used to analyze concentrations of neuronally derived small extracellular vesicles (NDE); significant differences in NDE profile were observed for kappa-opioid receptors when nicotine and cocaine were co-used compared with each drug alone and controls. These results suggest that drug interactions involving the co-use of nicotine and cocaine are not simply changing potency, but rather resulting in changes in reinforcing strength that should be utilized to better understand the neuropharmacology of CUD and the evaluation of potential treatments.