Synergistic effects of capsaicin and ketamine on the depression-like behaviors of animals subjected to the chronic unpredictable mild stress protocol

A significant percentage of depression patients are resistant to pharmacological treatments, highlighting the need for novel antidepressant strategies. Ketamine, an NMDA receptor antagonist, produces rapid antidepressant effects and is effective in treatment-resistant cases, but its association with cognitive and behavioral abnormalities resembling schizophrenia limits broader clinical utility. Capsaicin, a TRPV1 agonist, alone or combined with standard antidepressants, reduces immobility in the forced swim test (FST) in rodents. This study evaluated the effects of capsaicin and ketamine, isolated or combined treatments, in the chronic unpredictable mild stress (CUMS) model using multiple behavioral tests. We found immediate (day 1) and sustained (day 6) synergistic effects of capsaicin and ketamine in the FST after CUMS. The sucrose preference test (SPT) was performed on similar schedule. None of the treatments increased SPT on the last day of CUMS; however, capsaicin, ketamine, and their combination significantly increased SPT on day 6 post-CUMS, though pharmacologically treated groups did not reach SPT values of non-CUMS rats. Capsaicin alone and in combination with ketamine produced anxiolytic-like effects in the elevated plus maze and marble-burying tests. Locomotor activity in the open field test was unaffected by treatments, but all CUMS-exposed groups showed higher activity than non-CUMS animals. The most effective doses of capsaicin or the combination improved body weight and reduced adrenal gland hypertrophy, yet not to non-CUMS levels. These findings indicate that capsaicin plus ketamine exhibits synergistic antidepressant-like effects in the FST, sustains partial SPT recovery post-CUMS, and exerts anxiolytic-like actions.