Interaction effect of lithium and crocin on memory performance and behavioral functions in rats exposed to chronic unpredictable mild stress.

Chronic unpredictable mild stress (CUMS) is an approved method for the induction of depression in rodents. Lithium, as one of the oldest psychiatric drugs, can induce beneficial effects on mood state under stressful conditions. On the other hand, crocin (active component of Saffron) has antioxidant, procognitive, and mood-enhancer effects. In this study, we aimed to investigate the interaction effect of lithium and crocin on mood disturbances and cognitive impairments induced by CUMS. CUMS was performed for 3 weeks. Lithium (100 mg/kg, i.p.), or crocin (30 mg/kg, i.p.), or combination of both was injected during CUMS period (21 injections). Open field test, hot plate, forced swimming test, shuttle box, and Morris water maze were used to evaluate locomotor activity, pain perception, depressive-like behavior, passive avoidance memory, and spatial memory, respectively. The results showed that lithium decreased locomotion and climbing, increased pain threshold and immobility, and impaired passive avoidance and spatial memory in control rats. CUMS also showed all these effects, with more intensity. However, lithium partly reversed the effect of CUMS on locomotion and spatial memory, and completely restored the effect of CUMS on immobility and passive avoidance memory. Also, lithium did not change the effect of CUMS on pain threshold and climbing. Crocin alone, and in combination with lithium significantly reversed all the effects of CUMS. In conclusion, for the first time, the results of the present research showed that the combination of lithium and crocin leads to stronger therapeutic effects on mood disturbances and cognitive impairments induced by chronic stress.