Evaluating oral flavorant effects on nicotine self-administration behavior and phasic dopamine signaling

Abstract

Understanding how tobacco product flavor additives, such as flavorants in electronic cigarettes, influence smoking behavior and addiction is critical for informing public health policy decisions regarding tobacco product regulation. Here, we developed a combined intraoral (i.o.) and intravenous (i.v.) self-administration paradigm in rats to determine how flavorants influence self-administration behavior. By combining i.o. flavorant delivery with fast scan cyclic voltammetry (FSCV) or i.v. nicotine self-administration in adult, male rats, we examined whether flavors alter phasic dopamine (DA) signaling and nicotine self-administration. Oral administration of 10% sucrose or 0.32% saccharin, but not 0.005% menthol, increased phasic DA release in the nucleus accumbens (NAc). Oral sucrose or saccharin, when combined with i.v. nicotine delivery, also led to increased self-administration behavior. Specifically, combined i.o. sucrose and i.v. nicotine decreased responding compared to sucrose alone, and increased responding compared to nicotine alone. In contrast, i.o. flavorants did not alter motivational breakpoint in a progressive ratio task. Oral menthol, which did not alter i.v. nicotine administration, reversed oral nicotine aversion (50 and 100 mg/L) in a two-bottle choice test. Here, we demonstrate that i.o. appetitive flavorants that increase phasic DA signaling also increase self-administration behavior when combined with i.v. nicotine delivery. Additionally, oral menthol effects were specific to oral nicotine, and were not observed with i.v. nicotine-mediated reinforcement. Together, these preclinical findings have important implications regarding menthol and sweet flavorant additive effects on tobacco product use and can be used to inform policy decisions on tobacco product flavorant regulation.

Menthol facilitates dopamine-releasing effect of nicotine in rat nucleus accumbens

“…The doses of menthol (up to 5 mg/kg) that were used in the present study were shown to be effective in enhancing nicotine-taking and -seeking behavior in our previous studies (Biswas et al, 2016; Harrison et al, 2017), thus precluding possible concerns about the doses of menthol being too low to produce an effect. The lack of effect of menthol in this microdialysis assay is consistent with a recent report that showed that the intraoral administration of menthol, in contrast to sucrose or saccharin, produced no effect on phasic dopamine release, measured by fast-scan cyclic voltammetry, in the NAc (Wickham et al, 2018). A previous study found that menthol reduced the frequency of dopamine neuron firing in mouse brain slices and cultured neuron preparations (Henderson et al, 2016).…”

Evaluation of reinforcing and aversive effects of voluntary Δ9-tetrahydrocannabinol ingestion in rats

“…Rats and humans show affinity for sweet flavors and will readily drink solutions containing either sweetener (Hoffman et al, 2016; Murray et al, 2016). Further, consumption of sucrose or saccharin solution is associated with disruptions in dopamine signaling in the nucleus accumbens (Wickham et al, 2018), an effect that is also observed concomitant with self-administration of abused substances such as cocaine (Saddoris et al, 2016). Indeed, rodents have shown enhanced preference for oral consumption of sucrose solution compared to self-administration of several abused substances, including cocaine, heroin, and nicotine (Cantin et al, 2010; Huynh et al, 2017; Madsen and Ahmed, 2015).…”

Effects of active and passive smoking on salivary cytokines levels in rats: A pilot study

“…Several methods of cigarette smoke exposure have been adopted to establish animal models, such as the whole body, head only, nose only, intraoral nicotine self-administration, and intraoral or transdermal administration of tobacco smoke carcinogens. The whole body exposure to cigarette smoke, perfectly simulating human passive smoking, is the most commonly used approach (Al Hariri et al, 2016; Asci et al, 2018; Schick and Glantz, 2005; Wickham et al, 2018). However, to the best of our knowledge, the intraoral cigarette smoking exposure has not been reported to simulate human active smoking.…”