Analysis of sex differences in cisplatin-induced conditioned taste aversion

Chemotherapy-induced taste disorders and food aversion are important adverse effects that lead to reduced food intake and a deteriorated quality of life. Sex differences have been proposed to influence their development, but findings remain inconsistent, and no clinical consensus has been established. Further basic research is required to clarify these discrepancies underlying mechanisms. In this study, conditioned taste aversion (CTA) was evaluated in C57BL/6J mice after intraperitoneal administration of cisplatin, prepared in physiological saline, using a two-bottle choice test with distilled water and a saccharin-containing solution as drinking options. To assess the influence of saccharin on sweet taste sensitivity, four concentrations of saccharin-containing solutions were tested. A clear sex difference emerged during CTA development. Male mice showed reduced aversion at lower saccharin concentrations, that did not elicit preference, and no aversion at the lowest concentration. In contrast, female mice exhibited the onset of CTA even at concentrations that did not induce preference. Given reports of higher sweet-taste sensitivity in females, these findings suggest that CTA is driven by taste stimulation rather than taste preference. Additionally, female mice showed a lower propensity to develop CTA at 0.02% saccharin concentration than male mice. To investigate whether female sex hormones regulate CTA development, estradiol (E2) was administered subcutaneously before cisplatin treatment, followed by the same behavioral assessments. E2 administration ameliorated CTA, suggesting that E2 may facilitate the extinction of aversive learning. In summary, cisplatin-induced CTA appears to be triggered by taste stimulation itself, and E2 may represent a potential therapeutic approach for mitigating cisplatin-induced CTA.