Innate and acquired tolerance to bitter stimuli in mice

Tolerance to bitter foods and its potentiation by repetitive exposure are commonly experienced and potentially underlie the consumption of bitter foods, but it remains unknown whether permissive and adaptive responses are general phenomena for bitter-tasting substances or specific to certain substances, and they have not been rigorously studied in mice. Here, we investigated the effects of prolonged exposure to a bitter compound on both recognition and rejection behaviors to the same compound in mice. Paired measurements of rejection (R(j)T) and apparent recognition (aR(c)T) thresholds were conducted using brief-access two-bottle choice tests before and after taste aversion conditioning, respectively. First, R(j)T was much higher than aR(c)T for the bitter amino acids (L)-tryptophan and (L)-isoleucine, which mice taste daily in their food, indicating strong acceptance of those familiar stimuli within the concentration range between R(j)T and aR(c)T. Next, we tested five other structurally dissimilar bitter compounds, to which mice were naive at the beginning of experiments: denatonium benzoate, quinine-HCl, caffeine, salicin, and epigallocatechin gallate. R(j)T was moderately higher than aR(c)T for all the compounds tested, indicating the presence of innate acceptance to these various, unfamiliar bitter stimuli in mice. Lastly, a 3-week forced exposure increased R(j)T for all the bitter compounds except salicin, demonstrating that mice acquire tolerance to a broad array of bitter compounds after long-term exposure to them. Although the underlying mechanisms remain to be determined, our studies provide behavioral evidence of innate and acquired tolerance to various bitter stimuli in mice, suggesting its generality among bitterants.