Caffeine attenuates anxiety- and depressive-like behavior following cyclosporine administration in mice, possibly via an NO pathway

Physiol Behav. 2025 Oct 23:115142. doi: 10.1016/j.physbeh.2025.115142. Online ahead of print.

ABSTRACT

Cyclosporine (CyA) is the most common immunosuppressive medication used during organ transplantation, and its administration is associated with psychological adverse effects, including anxiety and depression. Furthermore, relationships between caffeine consumption and psychological illness have been documented. Nitric oxide (NO) signaling has an important role in the pathophysiology of depression as well as anxiety. Based on these, the current study aimed to investigate the possible contribution of the NO pathway in the caffeine effect on CyA-induced depressive- and anxiety-like behavior. The results showed that CyA administration (60 mg/kg) induced anxiety- and depressive-like behavior in male mice when assessed in the elevated plus maze (EPM) and forced swimming test (FST), respectively. Caffein at used doses (0-1 mg/kg) had no effect on anxiety- and depressive-like behavior. Pre-treatment of animals with caffeine (0.1 and 0.5 mg/kg) prevented CyA effects in EPM. Interestingly, caffeine at doses 0.5 and 1 mg/kg attenuated CyA-induced depression. Administration of L-arginine (25 mg/kg), a NO precursor, significantly attenuated the protective effect of caffeine on CyA in the FST, though this was not confirmed in the EPM. Furthermore, pretreatment with a NO synthase inhibitor, L-NAME (1 mg/kg), potentiated the protective effect of caffeine on CyA in the EPM. The present results demonstrated caffeine treatment prevented anxiety and depression induced by CyA, possibly partly via the NO signaling pathway.

PMID:41138988 | DOI:10.1016/j.physbeh.2025.115142