Chronic lithium exposure attenuates ketamine-induced mania-like behavior and c-Fos expression in the forebrain of mice.

Pretreatment with lithium moderates the effects of a single dose of ketamine on mania-like behavior and c-Fos expression in the mouse forebrain. Ketamine increased movement and induced higher c-Fos expression in several forebrain regions, including the lateral septal nucleus, hypothalamus, amygdala, and hippocampus. Chronic lithium treatment attenuated the ketamine-induced increase in movement and inhibited the rise in c-Fos-immunoreactive neurons in the dentate gyrus, CA1, dorsal and ventral subiculum, and amygdaloid nuclei. These findings may help understand mania episodes related to ketamine treatment for major depressive disorder and bipolar disorder.

Study at a glance

Abstract

Ketamine, a dissociative anaesthetic, has been used in the treatment of major depressive disorder (MDD) as a rapid acting antidepressant drug. Recent studies have shown that ketamine may increase the potential risk of treatment-induced mania in MDD patients. Lithium is a well-known mood stabilizer and has been widely used for the treatment of mania. It is not fully understood which forebrain regions are involved in ketamine- and lithium-induced expression of c-Fos. Therefore, our aim was to investigate the effect of chronic lithium treatment on mania-like behavior and c-Fos expression in the mouse forebrain activated by a single administration of ketamine. In the open field test, our results showed that ketamine significantly increased the total distance and total cumulative duration of movement in mice, while chronic lithium could attenuate these effects of ketamine. In addition, acute ketamine induced higher c-Fos expression in the lateral septal nucleus, hypothalamus, amygdala, and hippocampus of mice in the treatment group compared to those in the control group. However, chronic lithium inhibited the significant increase in c-Fos-immunoreactive neurons following acute ketamine administration in the dentate gyrus of the hippocampus, field CA1 of the hippocampus, dorsal subiculum, ventral subiculum, ventral subiculum, central amygdaloid nucleus and basolateral amygdaloid nucleus. In summary, our research shows that pretreatment with lithium moderates the effects of acute ketamine administration on mania-like behavior and c-Fos expression in the forebrain. These findings could be helpful in better understanding the episodes of mania related to ketamine treatment for MDD and bipolar disorder.