Ketamine is known to have a rapid and lasting antidepressant effect. Recent studies have shown that ketamine exerts it rapid antidepressant effect by blocking burst firing in the lateral habenula (LHb). Whether the sustained antidepressant effect of ketamine occurs through the same mechanism has not been explored. Here, using male rats, we found that local infusion of (R,S)-ketamine into the LHb resulted in a rapid antidepressant-like effect 1 hour after infusion, which almost returned to baseline levels after 24 hours. Intra-LHb injection of (S)-ketamine also showed a significant antidepressant-like effect 1 hour after injection, which recovered at 24 hours. No significant antidepressant-like effect was found at 1 hour or 24 hours after administration of (R)-ketamine into the LHb. Injection of (2R,6R)-hydroxynorketamine (HNK), a ketamine metabolite, into the LHb did not result in any obvious antidepressant-like effect 1 hour or 24 hours after injection. Systemic administration of (R,S)-ketamine (intraperi...