Cisplatin decreases voluntary wheel-running activity but does not impair food-motivated behavior in mice

Cisplatin is a chemotherapeutic agent that is still commonly used to treat solid tumors. However, it has several toxic side effects due in large part to the mitochondrial damage that it induces. As this mitochondrial damage is likely to result in a decrease in the amount of metabolic energy that is available for behavioral activities, it is not surprising that fatigue develops in cancer patients treated with cisplatin. The present preclinical study was initiated to determine whether the detrimental effects of cisplatin were more pronounced on physical effort requiring a lot of energy versus effort that not only requires less energy but also procures energy in the form of food. For this purpose, mice were either trained to run in a wheel or to work for food in various schedules of food reinforcement before being treated with cisplatin. The experiments were carried out only in male mice as we had already reported that sex differences in cisplatin-induced neurotoxicities are minimal. Cisplatin was administered daily for one cycle of five days, or two cycles separated by a five-day rest. As observed in previous experiments, cisplatin drastically reduced voluntary wheel running. In contrast, when cisplatin was administered to food-restricted mice trained to work for a food reward in a progressive ratio schedule or in a fixed-interval schedule, it tended to increase the number of responses emitted to obtain the food rewards. This increase was not associated with any change in the temporal distribution of responses during the interval between two reinforcements in mice submitted to the fixed interval schedule of food reinforcement. When cisplatin was administered to food-restricted mice trained in an effort-based decision-making task in which they had to choose between working for a grain pellet with little effort and working for a preferred chocolate pellet with more effort, it decreased the total number of responses emitted to obtain food rewards. However, this effect was much less marked than the decrease in wheel running induced by cisplatin. The decrease in the effort invested in the procurement of food rewards was not associated with any change in the relative distribution of effort between low reward and high reward during the time course of the test session. These findings show that cisplatin decreases energy-consuming activities but not energy-procuring activities unless they require a choice between options differing in their cost-benefit ratio. Furthermore, they indicate that the physical dimension of fatigue is more likely to develop in cisplatin-treated individuals than the motivational dimension of fatigue.