Development of animal models of treatment-resistant depression of rats

Psychoendocrinological studies have focused on the hypothalamic-pituitary- adrenal axis in patients with depression. We have already reported that in rats, repeated adrenocorticotropic hormone (ACTH) treatment blocks the effect of tricyclic antidepressants in decreasing immobility time in a forced swim test, a widely used animal experiment for predicting antidepressant activity. Furthermore, chronic coadministration of lithium or carbamazepine, an agent that potentiates the actions of antidepressants in patients with depression, including those with treatment-resistant depression, significantly decreased the duration of immobility, even when given concurrently with ACTH. Recently, clinical and animal studies have shown that neurogenesis/neuroprotection in the adult brain is important for the therapeutic actions of antidepressants. We indicated that repeated ACTH treatment decreased the expression of BDNFmRNA and the number of newborn cells in the rat hippocampus. Namely, we rec-ognized that ACTH-treated rats served as a useful animal model of tricyclic antidepressant treatment-resistant conditions.