Multiple biological processes are implicated in the neurobiology of depression based primarily on the characterization of antidepressant efficacy in na�ve rodents rather than on models that recapitulate the protracted feelings of anhedonia and helplessness that typify depression. In order to address this issue, the authors developed a protocol utilizing chronic oral exposure to the stress-associated adrenal hormone, corticosterone (CORT), in mice to induce anhedonic- and other depressive-like behaviors that are persistent for a significant duration of the animals’ lifespan, yet reversible by chronic antidepressant treatment. As we will discuss in this chapter, prior chronic CORT exposure has multiple behavioral consequences relevant to stress-related mood disorders despite normalization of blood serum CORT levels after weaning. An additional example (for which data are also provided) is persistently disrupted locomotor activity, suggestive of neurovegetative malaise and early waking, both characteristics of depression in humans. In sum, prior chronic CORT exposure provides an alternative method to chronic mild stress models of depression that is easily replicable and persistent, thereby modeling the chronic depressive-like state in humans.