The role of β-Nicotyrine in E-Cigarette abuse liability I: Drug Discrimination

Background{beta}-Nicotyrine ({beta}-Nic) is a unique minor alkaloid constituent in electronic nicotine delivery systems (ENDS) that is derived from nicotine (Nic) degradation and can reach 25% of Nic concentrations in ENDS aerosol. {beta}-Nic slows Nic metabolism and prolongs systemic Nic exposure, which may alter the discriminability of Nic. The present study sought to examine {beta}-Nic has interoceptive effects itself, and if it alters the subjective effects ENDS products within a drug-discrimination paradigm. MethodsThe pharmacodynamics of {beta}-Nic were examined in vitro, and a nicotine discrimination paradigm was used to determine if {beta}-Nic (0 - 5.0 mg/kg) shares discriminative stimulus properties with Nic (0.2 mg/kg) in male (n = 13) and female (n = 14) rats after 10- & 60-min {beta}-Nic pretreatment delays. A second group of rats was trained to discriminate {beta}-Nic and Nornicotine (Nornic) from saline to determine if {beta}-Nic alone has interoceptive properties and whether they are similar to Nornic. Results{beta}-Nic had similar binding affinity and efficacy at the 4{beta}2 nicotinic receptor subtype as Nornic, [~]50% of Nic efficacy. However, {beta}-Nic only weakly substituted for Nic during substitution testing in female rats, but not males, whereas Nornic fully substituted for Nic. Combination testing at the 10 and 60-min pretreatment intervals showed that {beta}-Nic dose-dependently increased the duration of nicotines discriminative stimulus effects, especially at the 60-min delay. Drug naive rats could reliably discriminate Nornic, but not {beta}-Nic, from Sal. Conclusion{beta}-Nic increased and prolonged the interoceptive stimulus properties of Nic, suggesting it may alter to the abuse liability of ENDS through its ability to slow Nic metabolism.