The Sustained Antidepressant Effects of Ketamine are Independent of the Lateral Habenula.

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 (intraperitoneal) significantly suppressed LHb bursting activity at 1 hour, but the inhibitory effect was reversed 24 hours after injection. No significant effect of (R,S)-ketamine on miniature excitatory postsynaptic potentials of LHb neurons was found at 1 hour or 24 hours after systemic application. Our study demonstrated that the sustained antidepressant-like effect of ketamine may not depend on burst firing of LHb neurons. SIGNIFICANCE STATEMENT Ketamine exerts it rapid antidepressant effect by blocking burst firing in the lateral habenula (LHb). However, whether the sustained antidepressant effect of ketamine occurs through the same mechanism has not been explored. In the present study, we demonstrated that the sustained antidepressant effect of ketamine may not depend on burst firing of LHb neurons. This finding may lead to a novel perspective on LHb in the antidepressant effect of ketamine.