Common green apple flavorant farnesene enhances nicotine reward


A common green apple vape flavor enhances nicotine reward and is also rewarding itself, according to research in mice recently published in eNeuro.

Vaping entices adolescents into nicotine use with fun flavors like green apple and cotton candy. Nicotine-free flavored vapes have also gained popularity.

But of the over 7000 available flavor chemicals, only a handful have been studied.

With or without nicotine, flavored vapes pose potential risks for the brain, including addiction.

To continue unravelling these risks, Cooper et al. gave mice either nicotine, the green apple flavorant farnesene, or both in one chamber and a saline solution in another.

Farnesene was rewarding by itself, as mice chose the farnesene chamber over the saline chamber.

But farnesene also enhanced reward when combined with nicotine.

The research team next measured how farnesene changed nicotine receptor expression and neuron activation. Alone, farnesene partially activated nicotinic receptors, meaning it may increase nicotine’s receptor activation when both substances are present.

Farnesene also increased the proportion of high- to low-sensitivity receptors.

A greater proportion of high-sensitivity receptors increases the effects of a standard nicotine dose, which could heighten reward and drug-seeking behavior.

Despite their marketing, vape flavors are not risk-free and may exacerbate the effects of nicotine.

While nicotine is the primary addictive component in tobacco products, additional flavors have become a concern with the growing popularity of electronic nicotine delivery systems (ENDS).

For this reason, we have begun to investigate popular tobacco and ENDS flavors. Here, we examined farnesol, a chemical flavorant used in green apple and fruit flavors in ENDS e-liquids, for its ability to produce reward-related behavior.

Using male and female 3-6 month old C57BL/6 J mice and farnesol doses of 0.1, 1, and 10 mg/kg we identified a sex-dependent effect in a conditioned place preference assay: farnesol-alone produces reward-related behavior in only male mice.

Despite this sex-dependent effect, 1.0 mg/kg farnesol enhances locomotor activity in both male and female mice.

To understand farnesol’s effect on reward-related behavior, we used whole-cell patch-clamp electrophysiology and confocal microscopy to investigate changes in putative dopamine and GABA neurons. For these approaches, we utilized genetically modified mice that contain fluorescent nicotinic acetylcholine receptors (nAChRs).

Our electrophysiological assays with male mice revealed that farnesol treatment increases ventral tegmental area (VTA) dopamine neuron firing frequency and this may be due to a decrease in inhibitory tone from GABA neurons.

Our microscopy assays revealed that farnesol treatment produces a significant upregulation of α6* nAChRs in male mice but not female mice. This was supported by an observed increase in α6* nAChR function in additional electrophysiology assays.

These data provide evidence that popular tobacco flavorants may alter smoking-related behavior and promote the need to examine additional ENDS flavors.



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