Distinct cognitive and discriminative stimulus effects of ketamine enantiomers in rats

• Published in: Pharmacology, biochemistry and behavior biochemistry and behavior, 2020-10, Vol.197, p.173011, Article 173011
• Main Authors: Popik, Piotr, Khoo, Shaun Yon-Seng, Kuziak, Agata, Golebiowska, Joanna, Potasiewicz, Agnieszka, Hogendorf, Adam, Popik, Oskar, Matloka, Mikolaj, Moszczynski, Rafal, Nikiforuk, Agnieszka, Witkin, Jeffrey M.
• Format: Article
• Language: English
• Subjects: Animals; Cognition - drug effects; Discrimination Learning - drug effects; Discrimination, Psychological - drug effects; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists - chemistry; Excitatory Amino Acid Antagonists - pharmacology; Executive Function - drug effects; Ketamine - chemistry; Ketamine - pharmacology; Male; Rats; Rats, Sprague-Dawley; Reaction Time - drug effects; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Stereoisomerism
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/j.pbb.2020.173011

Although (S)-ketamine was approved for use in treatment-resistant depression in 2019, new preclinical findings suggest that (R)-ketamine might produce better efficacy and tolerability relative to (S)-ketamine. Here we evaluated the effects of (R)-, (S)-, and (R,S)-ketamine on executive functions as measured in the attentional set shifting task (ASST) and on their discriminative stimulus effects in rats. Earlier data demonstrated that cognitive flexibility is compromised by (R,S)-ketamine, but the effects of enantiomers in rats are unknown. Separate cohorts of rats were tested in ASST and trained to discriminate either (R,S)-ketamine, (S)-ketamine, or (R)-ketamine (all at 10 mg/kg) from saline; in order to maintain the discrimination, a higher (R)-ketamine dose (17.5 mg/kg) was subsequently instituted. In ASST, all three forms increased the trials to criterion measure at reversal learning and extra-dimensional set-shifting phases. However, in contrast to (R)- and (S)-ketamine, (R,S)-ketamine prolonged the mean time to complete a single trial during early stages, suggesting increased reaction time, and/or unspecific side-effects related to motor or motivational impairments. In the drug discriminations, all rats acquired their respective discriminations between drug and saline. In (R,S)-ketamine-trained rats, (R)-ketamine and (S)-ketamine only partially substituted for the training dose of (R,S)-ketamine. Further, (R)-ketamine did not fully substitute in rats trained to (S)-ketamine. The data suggest more serious cognitive deficits produced by (R,S)-ketamine than its enantiomers. Furthermore, (R,S)-ketamine and its isomers share overlapping but not isomorphic discriminative stimulus effects predicting distinct subjective responses to (R)- vs. (S)-ketamine in humans. •Cognitive and discriminative stimulus effects of ketamine enantiomers were studies in rats.•Executive functions were measured in the attentional set shifting task.•Cognition: RS-ketamine was more impairing than enantiomers.•Ketamine enantiomers share overlapping but not isomorphic discriminative stimulus effects.