Roles of the monoaminergic system in the antidepressant effects of ketamine and its metabolites

While the molecular target of (R,S)-ketamine (ketamine) is thought to be the NMDA receptor, subanesthetic doses of ketamine have been known to modulate monoaminergic neurotransmission in the central nervous system. Although the involvement of the serotonergic system in the antidepressant effects of ketamine has been reported in most studies of this topic, some recent studies have reported that the dopaminergic system plays a key role in the effects of ketamine. Additionally, several lines of evidence suggest that the antidepressant-like effects of (R)-ketamine might be independent of the monoaminergic system. Ketamine metabolites also differ consid-erably in their ability to regulate monoamine neurotransmitters relative to (S)-ketamine and (R)-ketamine, while (2R,6R)-hydroxynorketamine might share common serotonergic signaling mechanisms with ketamine. In the current review, we summarize the effects of ketamine and its metabolites on monoamine neurotransmission in the brain and discuss the potential roles of the monoaminergic system in the mechanism of action of ketamine.