(R)-Ketamine exerts antidepressant actions partly via conversion to (2R,6R)-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)-d2 -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)-d2 -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)-d2 -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.

• Authors: Panos Zanos, Jaclyn N Highland, Xin Liu, Timothy A Troppoli, Polymnia Georgiou, Jacqueline Lovett, Patrick J Morris, Brent W Stewart, Craig J Thomas, Scott M Thompson, Ruin Moaddel, Todd D Gould
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 176 Issue 14 Pg. 2573-2592 (07 2019) ISSN: 1476-5381 [Electronic] England
• PMID: 30941749 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2019 The British Pharmacological Society.

Chemical References

• Anesthetics
• Antidepressive Agents
• Receptors, N-Methyl-D-Aspartate
• Ketamine

Topics

• Anesthetics (adverse effects, chemistry, metabolism)
• Animals
• Antidepressive Agents (adverse effects, chemistry, metabolism)
• Behavior, Animal (drug effects)
• Depression (drug therapy)
• Dose-Response Relationship, Drug
• Female
• Infusions, Intraventricular
• Ketamine (adverse effects, analogs & derivatives, metabolism)
• Male
• Mice
• Receptors, N-Methyl-D-Aspartate (antagonists & inhibitors, metabolism)
• Stereoisomerism