Preclinical Assessment of the Abuse Potential of the Isomers of Ketamine

Background: Racemic (R,S)‐ ketamine produces a rapid and long‐lasting antidepressant response in treatment resistant patients with major depressive disorder (MDD). However, the production of psychotomimetic effects and a propensity for abuse have limited its therapeutic use. The individual isomers of ketamine are being investigated for treatment of MDD with proponents stating each isomer has an improved side‐effect profile relative to the racemate. The goal of this project was to evaluate the abuse‐related behavioral side effects of (S) ‐ and (R) ‐ketamine by determining their reinforcing effects in a self‐administration procedure and (R,S) ‐ketamine‐like subjective effects in a drug discrimination procedure.

Methods: For the drug discrimination study, subjects were male Sprague‐Dawley rats trained to discriminate 5.6 mg/kg ketamine from saline in standard two‐lever operant chambers during daily 15‐min sessions. Correct responding was reinforced with food pellet delivery under a fixed ratio (FR) 10 schedule. Generalization tests with saline or different doses of (S) ‐ketamine (0.3 – 10 mg/kg), (R)‐ ketamine (3 mg/kg – 30 mg/kg) and (R,S) ‐ketamine (0.3 – 5.6 mg/kg) were conducted twice weekly with training sessions intervening. For the self‐administration study, subjects were four male Rhesus monkeys (Macaca mulatta) surgically implanted with a chronic catheter in a major vein. Monkeys were trained to respond for intravenous infusions of 56 μg/kg/inf (R,S) ‐ketamine solution under a FR 30 schedule. Solutions of saline or different doses of (R,S) ‐ketamine (10 to 170 μg/kg/inf ) and (S) ‐ketamine (10 to 100 μg/kg/inf ) were substituted for the training solution for four consecutive sessions. Any dose which maintained responding above saline levels was also tested under a progressive ratio schedule across sessions.

Results: In the discrimination procedure, the racemate and both isomers dose‐dependently generalized from the training dose with one or more doses producing full substitution. Comparing ED 50 values, (S) ‐ketamine was approximately 1.9‐fold more potent than ( R,S) ‐ketamine and 4‐fold more potent than (R) ‐ketamine for substitution and rate suppression. In the self‐administration study, one or more doses of the racemate and both isomers maintained levels of responding significantly above saline levels. When the work requirement was increased, both isomers maintained self‐administration behavior across a number of sessions with break points, the highest ratio maintaining responding above mean saline levels, reaching up to 200 responses/infusion.

Conclusions: The data show that both (R) ‐ and (S) ‐ketamine share discriminative stimulus effects with (R,S) ‐ketamine and therefore would be predicted to produce racemic ketamine‐like subjective effects in humans. In the self‐administration procedure, both (R) ‐ and (S) ‐ketamine serves as positive reinforcers of behavior under FR conditions with peak intake levels and break points comparable to the racemic form. Overall, based on these outcomes we would predict that both of the ketamine isomers would produce use‐limiting side effects similar to (S,R) ‐ketamine, including psychotomimetic effects and abuse liability, in humans. Support or Funding Information NIDA grant R01 DA037287 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .