Glucagon-like peptide-2 but not imipramine exhibits antidepressant-like effects in ACTH-treated mice.

We investigated the effectiveness of glucagon-like peptide-2 (GLP-2) against refractory depression in adrenocorticotropic hormone (ACTH)-treated mice as a model of tricyclic antidepressant (TCA)-resistant depression. Chronic ACTH treatment (0.45 mg/kg, s.c., 14 days) weakened the antidepressant-like effects of imipramine (20 mg/kg, i.p., 6 days) in the forced-swim test (FST). Conversely, GLP-2 (3 μg/mice, i.c.v., 6 days) induced antidepressant-like effects in the ACTH-treated mice in the FST. ACTH-treatment increased basal serum corticosterone levels, with an additional increase induced by the FST. Imipramine or GLP-2 had no effect on the basal corticosterone level, but GLP-2 attenuated the additional increase caused by the FST. Moreover, GLP-2 increased 5-HT levels, but not 5-HIAA. These results suggest that GLP-2 induced antidepressant-like effects under imipramine-resistant conditions through increase in 5-HT levels.