Oral ketamine alleviates behavioral despair without cognitive impairment in Wistar rats

Ketamine is a non-competitive NMDA receptor antagonist used as a major anesthetic agent, especially in children. It has also been shown that at sub-anesthetic concentrations, ketamine has acute antidepressant properties. The rapid-onset nature of this effect makes it a promising alternative for classical antidepressants targeting the monoaminergic system. However, ketamine can lead to various cognitive side effects depending on the user/subject as well as its concentration and administration method, and it is still questionable whether this drug can be utilized as a reliable antidepressant. Here, we test the effects of continuous low dose oral ketamine on behavioral despair and spatial working memory in male Wistar rats. We found that 0.4 mg/day, but not 0.2 mg/day, ketamine in 30 ml juice has an antidepressant effect emerging in just 10 consecutive days as measured by means of forced swim tests without impairing spatial working memory performance in the Y-maze for as long as 30 days. These results suggest that, once clinically optimized, long-term use of low dose oral ketamine can produce antidepressant effects.