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

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.