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

Abstract

Menthol is a significant flavoring additive in tobacco products. Accumulating clinical evidence suggests that menthol may promote tobacco smoking and nicotine dependence. Our previous studies demonstrated that menthol enhanced nicotine reinforcement in rats. However, it is unclear whether menthol interacts with nicotine at the neurochemical level. The present study used intracranial microdialysis to examine whether and the ways in which menthol affects nicotine-induced dopamine release in rats in the nucleus accumbens core (NAc), a terminal field of brain reward circuitry. To make comparisons with our previous work that showed an enhancing effect of menthol on nicotine self-administration behavior, male Sprague-Dawley rats were first trained in 20 daily 1-h sessions to press a lever for intravenous nicotine self-administration (15 μg/kg/infusion). Dopamine levels were then measured in the right NAc using intracranial microdialysis coupled with high-performance liquid chromatography. Five minutes before microdialysis, the rats received an intraperitoneal injection of menthol (0, 1, 2.5, and 5 mg/kg), a subcutaneous injection of nicotine (0.2 mg/kg or its vehicle), or both. Menthol alone did not affect dopamine levels in dialysates, whereas nicotine alone elevated dopamine levels. Combined nicotine and menthol administration significantly increased dopamine levels compared with nicotine alone. These data indicate a facilitating effect of menthol on nicotine-induced dopamine release in the NAc. These findings shed light on our understanding of the neurobiological mechanisms that underlie the menthol-induced enhancement of nicotine reinforcement.

Green Apple e-Cigarette Flavorant Farnesene Triggers Reward-Related Behavior by Promoting High-Sensitivity nAChRs in the Ventral Tegmental Area

“…Menthol is the most prominent flavor for tobacco products and was considered to be an inert flavor additive, yet, studies have shown that menthol enhances nicotine reward-related and reinforcement-related behaviors in rodents ( Wang et al, 2014 ; Biswas et al, 2016 ; Henderson et al, 2017 ). The menthol-induced enhancement is because of a combination of effects on nicotinic acetylcholine receptor (nAChR) upregulation ( Brody et al, 2013 ; Henderson et al, 2016 , 2017 ), dopamine neuron excitability ( Henderson et al, 2018 ), dopamine release ( Zhang et al, 2018 ), and TrpM8-dependent mechanisms ( Fan et al, 2016 ). In addition to menthol, similar investigations into other popular ENDS flavors are being conducted.…”

K48-Linked Ubiquitination Contributes to Nicotine-Augmented Bone Marrow-Derived Dendritic-Cell-Mediated Adaptive Immunity

“…Whereas the inhibition of dopamine receptor D3 signaling in DC increases antigen cross-presentation [ 33 ], dopamine-dependent behavioral effects of nicotine were also documented [ 34 ]. As nicotine treatment inhibits proteasomal activities [ 12 ] and increased dopamine release [ 35 ], the phenomena that WT-Ub fails to restore the ubiquitination-induced effects might be due to nicotine-increased dopamine release and the potential role of dopamine receptor D3 signaling in DC cross-presentation.…”

Novel Putative Positive Modulators of α4β2 nAChRs Potentiate Nicotine Reward-Related Behavior

“…In recent years, the direct effects of menthol on nAChRs have begun to be identified. Menthol enhances the nicotine-induced upregulation of nAChRs [ 19 , 20 ] and enhances reward-related behavior in conditioned place preference assays [ 19 ], the vapor self-administration of nicotine [ 21 ], intravenous self-administration of nicotine [ 16 , 22 ], and nucleus accumbens dopamine release [ 23 ]. These findings support the previous findings that menthol may be a cue-reinforcer for nicotine use [ 24 ].…”