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Br J Pharmacol. 2019 Jul;176(14):2573-2592. doi: 10.1111/bph.14683. Epub 2019 May 13.

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

Author information

1
Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
2
Program in Toxicology, University of Maryland School of Medicine, Baltimore, MD, USA.
3
Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.
4
Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
5
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
6
Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA.
7
Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA.
8
Veterans Affairs Maryland Health Care System, Baltimore, MD, USA.

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.

PMID:
30941749
DOI:
10.1111/bph.14683

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