Ketamine, a racemic mixture of (S)-ketamine and (R)-ketamine enantiomers, has been used as an anesthetic, analgesic and more recently, as an antidepressant. However, ketamine has known abuse liability (the tendency of a drug to be used in non-medical situations due to its psychoactive effects), which raises concerns for its therapeutic use. (S)-ketamine was recently approved by the United States’ FDA for treatment-resistant depression. Recent studies showed that (R)-ketamine has greater efficacy than (S)-ketamine in preclinical models of depression, but its clinical antidepressant efficacy has not been established. The behavioral effects of racemic ketamine have been studied extensively in preclinical models predictive of abuse liability in humans (self-administration and conditioned place preference [CPP]). In contrast, the behavioral effects of each enantiomer in these models are unknown. We show here that in the intravenous drug self-administration model, the gold standard procedure to assess potential abuse liability of drugs in humans, rats self-administered (S)-ketamine but not (R)-ketamine. Subanesthetic, antidepressant-like doses of (S)-ketamine, but not of (R)-ketamine, induced locomotor activity (in an opioid receptor-dependent manner), induced psychomotor sensitization, induced CPP in mice, and selectively increased metabolic activity and dopamine tone in medial prefrontal cortex (mPFC) of rats. Pharmacological screening across thousands of human proteins and at biological targets known to interact with ketamine yielded divergent binding and functional enantiomer profiles, including selective mu and kappa opioid receptor activation by (S)-ketamine in mPFC. Our results demonstrate divergence in the pharmacological, functional, and behavioral effects of ketamine enantiomers, and suggest that racemic ketamine’s abuse liability in humans is primarily due to the pharmacological effects of its (S)-enantiomer.
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This work was supported by NIDA (ZIA000069), NIMH, and NINDS intramural funds. We thank Drs. Marisela Morales (NIDA/IRP), Dr. David White (NIDA/MDTB), Martin Pomper (Johns Hopkins University) and Robert Dannals (Johns Hopkins University) for providing resources and equipment that made this work possible. We also thank the technical support provided by Theresa Kopajtic, Hannah Korah and Sarah Applebey in helping us set up experimental procedures.
Conflict of interest
CAZ is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation. CAZ is listed as co-inventor on a patent for the use of (2R,6R)- hydroxynorketamine, (S)-dehydronorketamine, and other stereo- isomeric dehydro and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as a co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and posttraumatic stress disorders. He has assigned his patent rights to the US government but will share a percentage of any royalties that may be received by the government. All other authors declare no conflict of interest.
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Bonaventura, J., Lam, S., Carlton, M. et al. Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability. Mol Psychiatry 26, 6704–6722 (2021). https://doi.org/10.1038/s41380-021-01093-2
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