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Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability

2022.01.16.

Jordi Bonaventura, Sherry Lam, [...], and Michael Michaelides, Mol Psychiatry, 2021

Abstract

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.

Results from nanoScan PET/CT

  • Authors' results extend prior findings by demonstrating the selective contribution of each enantiomer to discrete in vivo brain metabolic activity signatures:
    • (S)-ketamine selectively increased activity in the medial prefrontal cortex (mPFC) (one-way ANOVA; T(1,7)>1.89, p ≤ 0.05) whereas (R)-ketamine did not
    • (R)-ketamine selectively decreased in activity in the mediodorsal nuclei of the thalamus, including the paraventricular and habenular regions (one-way ANOVA; T(1,7)>1.89, p ≤ 0.05) whereas (S)-ketamine did not Figures 3B-C

Figures 3 A to C, (S)- or (R)-ketamine infusions (15mg/kg/h) have differential effects on metabolic activity evaluated as accumulation and trapping of [18F]FDG in the brains of awake, freely-moving rats. The rats were anesthetized and scanned 40 min after drugs and [18F]FDG (decay half-life =~110 min) were administered, providing a “snapshot” of metabolic activity during the awake, freely-moving state. Brain-wide voxel-based analysis was used to evaluate differences on activity using a one-way ANOVA. Color shaded areas in B and C represent clusters of voxels (≥100) with significant (p<0.05) increases or decreases in metabolic rate compared to saline infusions.

 

  • Neither (S)- nor (R)-ketamine significantly changed global extracellular dopamine levels in the dorsal striatum Figures 3 I-J
  • In contrast, other midbrain dopamine projection sites such as mPFC, septum, and globus pallidus showed increased [18F]fallypride displacement, (i.e., higher dopamine tone) in rats infused with (S)-ketamine, whereas somatosensory cortex and nucleus accumbens showed higher dopamine tone when rats were infused with (R)-ketamine (one-way ANOVA; T(1,18)>1.73, p ≤ 0.05) (Figure 3K).

Figure 3 (G). After ketamine and [18F]fallypride animals were anesthetized and a static PET image was acquired for 30 minutes (G). PET images (I-J) were analyzed using both region of interest-wise and voxel-wise analysis methods. In K, shaded areas represent clusters of voxels (≥100) with significant (p<0.05) increases or decreases in dopamine tone between (S)- and (R)-ketamine. Abbreviations: CPu, Caudate-Putamen; Acb, Nucleus Accumbens; Pit, Pituitary gland.

 

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