β-Nicotyrine and e-cigarette abuse liability I: Pharmacodynamics and interaction with pharmacokinetics and discriminative stimulus effects of nicotine in rats.

Abstract

β-Nicotyrine (β-Nic) is a prevalent minor alkaloid in electronic nicotine delivery systems (ENDS) aerosols. High doses of β-Nic slow nicotine (Nic) metabolism in mice, suggesting it may alter the abuse liability of ENDS. Thus, the present study examined the pharmacokinetics and pharmacodynamics of β-Nic and Nic, both alone and in combination, including the ability of β-Nic to produce nicotine-like discriminative-stimulus (i.e., subjective) effects and/or enhance the effects of Nic in rats. Unlike Nic and Nornicotine (Nornic) which bound to and activated acetylcholine receptors (α2β2, α3β4, α4β2) in vitro, β-Nic did not bind to these receptors, nor did it bind to a range of noncholinergic receptors (e.g., dopamine, GABA). A clinically relevant β-Nic dose (i.e., 25 % of Nic) slowed Nic clearance by ~50 %. In rats trained to discriminate Nic (0.2mg/kg) from Saline (Sal), β-Nic alone weakly substituted for Nic in females, but not males, whereas Nornic substituted for Nic in both sexes. Combinations of Nic + β-Nic increased the discriminability of Nic when administered 10- and 60-min prior to testing. Drug naïve rats learned to discriminate Nornic, but not β-Nic, from Sal. β-Nic slows Nic clearance in rats and enhances and prolongs the discriminative stimulus effects of Nic, suggesting it may contribute to the abuse liability of ENDS.