Background and Aim: Depression is a mood disorder with high global prevalence. Depression is associated
with a reduction in the hippocampal volume and change in its neurotransmitters function. Trigonelline is an
alkaloid with neuroprotective activity. The aim of this study was to investigate the possible role of N-methyl-Daspartate
(NMDA) receptor in the antidepressant-like effect of trigonelline, considering histopathological modifications
of the hippocampus.
Methods: 60 Naval Medical Research Institute (NMRI) male mice were divided into 6 groups including group 1
(normal saline), groups 2, 3 and 4 (trigonelline at doses of 10, 50 and 100 mg/kg), group 5 (effective dose of
trigonelline plus NMDA agonist) and group 6 (sub-effective dose of trigonelline plus NMDA antagonist). Forced
swimming test (FST) was used to assess depressive-like behavior. Hippocampi were separated under deep anesthesia
and used for histopathological evaluation as well as NMDA receptor gene expression assessment.
Results: Trigonelline at doses of 10, 50 and 100 significantly reduced the immobility time in the FST in comparison
to the control group. The administration of the sub-effective dose of trigonelline plus ketamine (an NMDA
receptor antagonist) potentiated the effect of the sub-effective dose of trigonelline. In addition, co-treatment of an
effective dose of trigonelline with NMDA mitigated the antidepressant-like effect of trigonelline. Trigonelline at
doses of 50 and 100 mg/kg significantly increased the diameter of the CA1 area of the hippocampus.
Conclusion: Trigonelline showed an antidepressant-like effect in mice, probably via attenuation of NMDA receptor
activity and an increase in the CA1 region of the hippocampus.