Efects of ketamine optical isomers, psilocybin, psilocin and norpsilocin on time estimation and cognition in rats

Abstract

Rationale Ketamine and psilocybin belong to the rapid-acting antidepressants but they also produce psychotomimetic efects including timing distortion. It is currently debatable whether these are essential for their therapeutic actions. As depressed patients report that the “time is dragging,” we hypothesized that ketamine and psilocybin-like compounds may produce an opposite efect, i.e., time underestimation, purportedly contributing to their therapeutic properties. Objectives Timing was tested following administration of (R)- and (S)-ketamine, and psilocybin, psilocin, and norpsilocin in the discrete-trial temporal discrimination task (TDT) in male rats. Timing related to premature responses, and cognitive and unspecifc efects of compounds were tested in the 5-choice serial reaction time task (5-CSRTT) in the standard 1-s, and “easier” 2-s stimulus duration conditions, as well as in the vITI variant promoting impulsive responses. Results (S)-ketamine (15 but not 3.75 or 7.5 mg/kg) shifted psychometric curve to the right in TDT and reduced premature responses in 5-CSRTT, suggesting expected time underestimation, but it also decreased the accuracy of temporal discrimination and increased response and reward latencies, decreased correct responses, and increased incorrect responses. While (R)-ketamine did not afect timing and produced no unspecifc actions, it reduced incorrect responses in TDT and increased accuracy in 5-CSRTT, suggesting pro-cognitive efects. Psilocin and psilocybin produced mainly unspecifc efects in both tasks, while norpsilocin showed no efects. Conclusions Time underestimation produced by (S)-ketamine could be associated with its antidepressant efects; however, it was accompanied with severe behavioral disruption. We also hypothesize that behavioral disruption produced by psychedelics objectively refects their psychotomimetic-like actions.