Sex and age differences in mice models of effort-based decision-making and anergia in depression: the role of dopamine, and cerebral-dopamine-neurotrophic-factor

Mesolimbic dopamine (DA) regulates vigor in motivated behavior. While previous results have mainly been performed in male rodents, the present studies compared CD1 male and female mice in effort-based decision-making tests of motivation. These tests offered choices between several reinforcers that require different levels of effort (progressive ratio/choice task and 3-choice-T-maze task). Sweet reinforcers were used in both tasks. In the operant tasks, females worked harder as the task required more effort to access a 10% sucrose solution. Although males and females did not differ in preference for 10% vs 3% solutions under free concurrent presentation, females consumed more of the 10% solution when tested alone. The operant task requires a long period of training and changes in the DA system due to age can be mediating long-term changes in effort. Thus, age and sex factors were evaluated in the T-maze task, which requires only a short training period. Both sexes and ages were equally active when habituated to the running wheel (RW), but females consumed more sweet pellets than males, especially at an older age. Both sexes had a strong preference for the RW compared to more sedentary reinforcers in the 3-choice-T-maze test, but older animals spent less time running and ate more than the young ones. The DA-depleting agent tetrabenazine reduced time running in older mice but not in adolescents. Cerebral-dopamine-neurotrophic-factor was reduced in older mice of both sexes compared to adolescent mice. These results emphasize the importance of taking into account differences in sex and age when evaluating willingness to exert effort for specific reinforcers.