Abuse liability assessment of an e-cigarette refill liquid using intracranial self-stimulation and self-administration models in rats

Abstract

Background The popularity of electronic cigarettes (ECs) has increased dramatically despite their unknown health consequences. Because the abuse liability of ECs is one of the leading concerns of the Food and Drug Administration (FDA), models to assess it are urgently needed to inform FDA regulatory decisions regarding these products. The purpose of this study was to assess the relative abuse liability of an EC liquid compared to nicotine alone in rats. Because this EC liquid contains non-nicotine constituents that may enhance its abuse liability, we hypothesized that it would have greater abuse liability than nicotine alone. Methods Nicotine alone and nicotine dose-equivalent concentrations of EC liquid were compared in terms of their acute effects on intracranial self-stimulation (ICSS) thresholds, acquisition of self-administration, reinforcing efficacy (i.e., elasticity of demand), blockade of these behavioral effects by mecamylamine, nicotine pharmacokinetics and nicotinic acetylcholine receptor binding and activation. Results There were no significant differences between formulations on any measure, except that EC liquid produced less of an elevation in ICSS thresholds at high nicotine doses. Conclusions Collectively, these findings suggest that the relative abuse liability of this EC liquid is similar to that of nicotine alone in terms of its reinforcing and reinforcement-enhancing effects, but that it may have less aversive/anhedonic effects at high doses. The present methods may be useful for assessing the abuse liability of other ECs to inform potential FDA regulation of those products.

Similar precipitated withdrawal effects on intracranial self-stimulation during chronic infusion of an e-cigarette liquid or nicotine alone

“…However, our data are consistent with findings indicating that acute injections of low to moderate doses of these EC liquids and nicotine alone produced similar ICSS threshold-lowering (reinforcement-enhancing) effects (LeSage et al 2016, Harris et al submitted), and that Aroma E-Juice EC liquid and nicotine alone had similar reinforcing effects in an i.v. self-administration model (LeSage et al, 2016). Complementing our findings, degree of nicotine addiction and withdrawal in humans was no greater for ECs than for nicotine gum (Etter and Eissenberg, 2015).…”

“…The similar effects of nicotine alone and EC liquids in this study contrast with findings indicating that these 3 EC liquids produced less ICSS threshold-elevating (aversive / anhedonic) effects than nicotine alone at a high acute nicotine dose (LeSage et al, 2016; Harris et al, submitted), and suggest different mechanisms underlying ICSS threshold elevations induced by acute versus chronic nicotine exposure (see also Fowler et al, 2013). However, our data are consistent with findings indicating that acute injections of low to moderate doses of these EC liquids and nicotine alone produced similar ICSS threshold-lowering (reinforcement-enhancing) effects (LeSage et al 2016, Harris et al submitted), and that Aroma E-Juice EC liquid and nicotine alone had similar reinforcing effects in an i.v.…”

“…Aroma E-Juice Whole Tobacco Alkaloid (WTA) EC refill liquid (Dark Honey Tobacco flavor), Janty EC refill liquid (DK Port flavor), and NicVape EC refill liquid (Fruit Stripe Gum / Fruit Twist flavor) were obtained from Aroma E-Juice (http://www.aromaejuice.com, Scottsdale, AZ), Janty USA (http://www.usa.janty.com, Blasdell, NY), and NicVape (http://www.nicvape.com, Spartanburg, SC), respectively. These EC liquids were used because we have previously studied them in other preclinical addiction models (LeSage et al, 2016; Harris et al, submitted). In addition, Aroma E-Juice is advertised as containing higher levels of minor alkaloids than other ECs, and Janty and NicVape EC liquid contained relatively high (Janty) and low (NicVape,) levels of minor alkaloids relative to nicotine in our analysis of 20 different EC liquids (Harris et al, submitted).…”

“…The average measured nicotine concentration across vials for all 3 EC liquids was 22.88 ± 0.48 SEM mg/ml (range 21.5–25.9 mg/ml). When expressed as a percentage of nicotine, levels of total minor alkaloids (nornicotine + anabasine + anatabine) in Aroma E-Juice, Janty, and NicVape EC liquids were 1.15%, 2.28%, and 0.11%, respectively (LeSage et al, 2016; Harris et al, submitted). These labeled levels of nicotine, VG, and PG, and actual levels of nicotine and minor alkaloids, are within the typical range of those reported for EC liquids (Etter et al, 2013; Goniewicz et al, 2014; Han et al, 2016).…”

“…self-administration model (LeSage et al, 2016; Harris et al, submitted). In contrast, all three EC liquids produced less ICSS threshold-elevating effects than nicotine alone at a high acute nicotine dose, which may reflect a reduction in nicotine’s aversive/anhedonic effects (Fowler et al, 2011; Spiller et al, 2009).…”