Intragastric infusion of denatonium conditions flavor aversions and delays gastric emptying in rodents.

Because most naturally occurring toxins taste bitter to humans, any mechanism that reduces the rate at which bitter substances are ingested and digested should be adaptive. Based on the recent discovery of T2R bitter taste receptors in the gastrointestinal tract of rodents, we asked whether intragastric (IG) infusion of denatonium (a ligand for T2R receptors) would condition a flavor aversion and/or delay gastric emptying. Four experiments tested for post-oral responses to denatonium in rodents. First, Sprague-Dawley rats were trained to associate intake of a flavored solution (the CS+) with IG denatonium infusions, and intake of a different-flavored solution (the CS-) with IG water infusions during 30 min/day sessions. The rats acquired an aversion to the CS+ flavor when it was paired with IG infusions of 10 mM (but not 2.5 mM) denatonium. Intragastric infusions of 10 mM denatonium also delayed gastric emptying of food in the same rats. Second, we asked how long it took for rats to suppress their drinking while being infused IG with 10 mM denatonium. Rats drinking a palatable solution paired with IG infusions of 10 mM denatonium suppressed their licking within 6 min, as compared to rats infused IG with water. Third, we trained C57BL/6J (B6) mice 24 h/day to associate a CS+ flavor paired with IG infusions of 12 mM denatonium (diluted to 6 mM by orally consumed CS+). Like rats, the mice acquired a robust aversion to the CS+ flavor when it was paired with IG infusions of denatonium. A final experiment assessed the potential toxicity of denatonium. To this end, we gave B6 mice a 6 mM denatonium solution as their only source of water for 3 weeks. The mice grew normally and did not display any clinical signs of denatonium toxicosis. This study provides the first evidence that rodents respond to the presence of "bitter" substances in their gastrointestinal tract by generating both behavioral and physiological responses.