Approximately 30-60% of patients treated with existing antidepressants fail to achieve remission of depressive symptoms leading to Treatment Resistant Depression (TRD). There is an urgent need to develop novel medications, which is highly limited by the non-availability of relevant animal models with good predictive validity. ACTH administration has been shown to result in the resistance to acute and chronic effects of imipramine. However, the pharmacology of the model and the mechanisms contributing to the resistance are not completely understood. Furthermore, it is not known whether the ACTH administered animals show signs of depression-like behavior. Accordingly, we characterized the behavioral profile and sensitivity to antidepressants in BALB/c mice treated with ACTH and to evaluate some of the mechanisms responsible for the behavioral effects. Daily treatment with ACTH for 14, 21 or 28days failed to produce a depression-like phenotype in the sucrose preference test, voluntary wheel running or FST. In contrast, the acute antidepressant response in the FST was no longer observed in ACTH mice treated with fluoxetine, imipramine, duloxetine or bupropion. Interestingly, the combination of fluoxetine and a low dose of olanzapine, or the combination of fluoxetine and bupropion was efficacious in ACTH treated mice. Further, the sensitivity to a GluN2B receptor antagonist, radiprodil was retained in the ACTH model. To understand the mechanism responsible for the diminished response in these mice, we evaluated p11 (S100A10) mRNA expression and 5-HT2A protein expression. p11 expression was decreased and 5-HT2A protein content increased in ACTH treated mice. In summary, this model may have utility for the identification of novel treatments for TRD.