Lithium attenuates d‐amphetamine‐induced hyperlocomotor activity in mice via inhibition of interaction between cyclooxygenase‐2 and indoleamine‐2,3‐dioxygenase

In the present study, we investigated whether mood stabilizer lithium (Li) protects against d‐amphetamine (AMP)‐induced mania‐like behaviours via modulating the novel proinflammatory potential. Repeated treatment with AMP resulted in significant increases in proinflammatory cyclooxygenase‐2 (COX‐2) and indolemaine‐2,3‐dioxygenase‐1 (IDO)‐1 expression in the prefrontal cortex (PFC) of mice. However, AMP treatment did not significantly change IDO‐2 and 5‐lipoxygenase (5‐LOX) expression, suggesting that proinflammatory parameters such as COX‐2 and IDO‐1 are specific for AMP‐induced behaviours. AMP‐induced initial expression of COX‐2 (15 minutes post‐AMP) was earlier than that of IDO‐1 (1 hour post‐AMP). Mood stabilizer Li and COX‐2 inhibitor meloxicam significantly attenuated COX‐2 expression 15 minutes post‐AMP, whereas IDO‐1 inhibitor 1‐methyl‐DL‐tryptophan (1‐MT) did not affect COX‐2 expression. However, AMP‐induced IDO‐1 expression was significantly attenuated by Li, meloxicam or 1‐MT, suggesting that COX‐2 is an upstream molecule for the induction of IDO‐1 caused by AMP. Consistently, co‐immunoprecipitation between COX‐2 and IDO‐1 was observed at 30 minutes, 1, 3, and 6 hours after the final AMP treatment. This interaction was also significantly inhibited by Li, meloxicam or 1‐MT. Furthermore, AMP‐induced hyperlocomotion was significantly attenuated by Li, meloxicam or 1‐MT. We report, for the first time, that mood stabilizer Li attenuates AMP‐induced mania‐like behaviour via attenuation of interaction between COX‐2 and IDO‐1, and that the interaction of COX‐2 and IDO‐1 may be critical for the therapeutic intervention mediated by mood stabilizer.