Over the last two decades, our ever-increasing ability to manipulate the mouse genome has resulted in a variety of genetically defined mouse models of depression and other psychiatric and neurological disorders. However, it is still the case that some relevant rodent models for depression and antidepressant action have been validated experimentally in rats only and not in mice. An important example of such models is the operant model of antidepressant action known as differential-reinforcement-of-low-rates 72-second (DRL 72-s). A specific set of drug-induced changes on the performance of rats responding under a DRL 72-s schedule of reinforcement has been shown to be a highly reliable predictor of antidepressant activity in human depressive disorders. The aim of this study is to validate the use of the DRL 72-s schedule in mice by both genetic and pharmacological means. We have analyzed the actions of the specific serotonin reuptake inhibitor (SSRI) fluoxetine and the tricyclic agent desipramine (DMI) on wild-type and 5-hydroxytryptamine 1A receptor-null mutant (5-HT(1A)R KO) mice. In agreement with the literature on rats, we found that fluoxetine produced an acute antidepressant-like effect in 5-HT(1A)R KO mice but not in wild-type (Wt) mice. Additionally, an antidepressant-like effect was observed when DMI was administered to both 5-HT(1A)R KO and Wt mice. In conclusion: through the use of both genetic and pharmacological strategies, this study validates the extension of a protocol involving the DRL 72-s operant schedule of reinforcement as a behavioral model for the action of antidepressants in mice.