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Flavor additives facilitate oral self-administration of nicotine solution in mice



Tobacco products are very addictive, partly because they contain nicotine which is reinforcing, but also because they include appealing aromas and tastes. Flavor additives are such sensory stimuli which enhance attractiveness, as well as use and abuse of tobacco and vaping products. Yet, the interaction between these flavor additives and nicotine remains poorly understood.


We want to understand how flavors may reduce nicotine’ aversive taste and how it may enhance its voluntary oral self-administration in mice.


We first studied the effect of flavor additives on nicotine solution palatability in a free bottle choice paradigm. Second, we investigated the effect of vanilla flavoring on the different stages of nicotine (40 μg/ml) oral self-administration in mice.


We show that adding flavors increase nicotine palatability and facilitate acquisition and maintenance of oral self-administration when compared to nicotine-alone group. Mice adapt their operant behavior depending on changes in nicotine concentration. All mice reinstate nicotine seeking upon presentation of associated cues. Nevertheless, vanilla-flavored nicotine was not more reinforcing than vanilla-flavored water which was reinforcing enough to drive similar operant response rates.


Flavor additives increase nicotine oral consumption and help maintaining operant behavior in mice. Moreover, flavors can be very attractive and can have high reinforcing value by themselves. Thus, it is crucial that the investigation on how taste signals play an important role in modulating oral nicotine intake in rodent models remains explored.

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The authors thank Yoan Salafranque for the care provided to the mice during the experiments.


This study was supported by the Centre National de la Recherche Scientifique, the University of Bordeaux and Region Aquitaine and Institut National du Cancer (INCa 2019–016 to SC). ST was supported by the “Ministère de la Recherche et de l’Enseignement Supérieur”.

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Correspondence to Stephanie Caille.

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Fig. S1

Saccharin pretraining: oral self-administration of saccharin 0.1% solution. Performances are given with respect to the mice distribution during nicotine oral self-administration: vanilla 1% (grey bars and dots, n = 11), nicotine + vanilla 1% (black bars and dots, n = 12) and nicotine (white bars and dots, n = 12). a Number active and inactive nose-pokes (average over the last 3 sessions) and b number of rewards on the last day of training on FR2 schedule of reinforcement. *p < 0.05 main effect operant responding. All data are expressed as mean ± SEM (DOCX 7078 kb)

Fig. S2

Number of inactive nose-poke visits at different steps of nicotine oral self-administration for vanilla 1% (grey bars and dots, n = 11), nicotine + vanilla 1% (black bars and dots, n = 12), and nicotine (white bars and dots, n = 12) groups. Visits during a acquisition of fixed ratio schedules, b nicotine dose-response curve, and c progressive ratio test. *p < 0.05 Tukey multiple comparisons on groups. All data are expressed as mean ± SEM (DOCX 7658 kb)

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Tannous, S., Darlot, F., Cador, M. et al. Flavor additives facilitate oral self-administration of nicotine solution in mice. Psychopharmacology 238, 2235–2247 (2021).

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  • Addiction
  • Reward
  • Nicotine
  • Flavor
  • Oral self-administration
  • Free bottle choice
  • Mice