(<i>R</i>)‐Ketamine exerts antidepressant actions partly via conversion to (<i>2R,6R</i>)‐hydroxynorketamine, while causing adverse effects at sub‐anaesthetic doses

Abstract

Background and Purpose ( R )‐Ketamine (arketamine) may have utility as a rapidly acting antidepressant. While ( R )‐ketamine has lower potency than ( R,S )‐ketamine to inhibit NMDA receptors in vitro, the extent to which ( R )‐ketamine shares the NMDA receptor‐mediated adverse effects of ( R,S )‐ketamine in vivo has not been fully characterised. Furthermore, ( R )‐ketamine is metabolised to ( 2R,6R )‐hydroxynorketamine (HNK), which may contribute to its antidepressant‐relevant actions. Experimental Approach Using mice, we compared ( R )‐ketamine with a deuterated form of the drug (6,6‐dideutero‐( R )‐ketamine, ( R )‐d 2 ‐ketamine), which hinders its metabolism to ( 2R,6R )‐HNK, in behavioural tests predicting antidepressant responses. We also examined the actions of intracerebroventricularly infused ( 2R,6R )‐HNK. Further, we quantified putative NMDA receptor inhibition‐mediated adverse effects of ( R )‐ketamine. Key Results ( R )‐d 2 ‐Ketamine was identical to ( R )‐ketamine in binding to and functionally inhibiting NMDA receptors but hindered ( R )‐ketamine's metabolism to ( 2R,6R )‐HNK. ( R )‐Ketamine exerted greater potency than ( R )‐d 2 ‐ketamine in several antidepressant‐sensitive behavioural measures, consistent with a role of ( 2R,6R )‐HNK in the actions of ( R )‐ketamine. There were dose‐dependent sustained antidepressant‐relevant actions of ( 2R,6R )‐HNK following intracerebroventricular administration. ( R )‐Ketamine exerted NMDA receptor inhibition‐mediated behaviours similar to ( R,S )‐ketamine, including locomotor stimulation, conditioned‐place preference, prepulse inhibition deficits, and motor incoordination, with approximately half the potency of the racemic drug. Conclusions and Implications Metabolism of ( R )‐ketamine to ( 2R,6R )‐HNK increases the potency of ( R )‐ketamine to exert antidepressant‐relevant actions in mice. Adverse effects of ( R )‐ketamine require higher doses than those necessary for antidepressant‐sensitive behavioural changes in mice. However, our data revealing that ( R )‐ketamine's adverse effects are elicited at sub‐anaesthetic doses indicate a potential risk for sensory dissociation and abuse liability.