Effects of ketamine optical isomers, fluoxetine and naloxone on timing in differential reinforcement of low-rate response (DRL) 72-s task in rats.
Natalia Malikowska‐racia, Joanna Gołębiowska, Agnieszka Nikiforuk, Shaun Yon‐seng Khoo, Piotr Popik
European Neuropsychopharmacology February 2023 DOI: 10.1016/j.euroneuro.2022.11.007 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Male rats |
| Interventions | (S)-ketamine (R)-ketamine fluoxetine naloxone |
| Dose | (S)-ketamine 30-60 mg/kg; (R)-ketamine 30 and 60 mg/kg; fluoxetine 2.5-10 mg/kg |
| Topics | Esketamine Ketamine |
| Keywords | Drl 72-s Psychedelic Rapid antidepressant Ssri Time perception |
| Key findings | All three medications produced antidepressant-like effects on DRL 72-s performance, but only fluoxetine and (S)-ketamine induced time underestimation; (R)-ketamine did not affect timing. Naloxone pretreatment did not block the ketamine enantiomers' effects but unexpectedly potentiated fluoxetine's performance, which the authors argue warrants clinical investigation. |
Abstract
(S)-ketamine-induced rapid-acting antidepressant effects have revolutionized the pharmacotherapy of major depression; however, this medication also produces psychotomimetic effects such as timing distortion. While (R)-ketamine produces fewer dissociative effects, its antidepressant actions are less studied. Depression is associated with time overestimation (i.e., subjectively, time passes slowly). Our recent report suggests that while (S)-ketamine induces an opposite effect, i.e., time underestimation, the (R)-isomer does not affect timing. It has been suggested that opioid receptors are involved in the antidepressant effect of ketamine. In the present study we tested (R)- and (S)-ketamine, and fluoxetine as a positive control in the differential-reinforcement-of-low-rate (DRL) 72-s schedule of reinforcement in male rats following naloxone pretreatment. DRL classic metrics as well as peak deviation analyses served to determine antidepressant-like actions and those associated with timing. We report antidepressant-like effects of (S)-ketamine (30-60 mg/kg) that resemble fluoxetine's (2.5-10 mg/kg), as both compounds increased reinforcement rate and peak location (suggesting increased performance), reduced premature responses (suggesting time underestimation) and decreased Weber's fraction (suggesting increased timing precision). (R)-ketamine (30, but not 60 mg/kg) increased only the reinforcement rate and peak location but did not affect timing. Only fluoxetine decreased burst responses, suggesting decreased impulsivity. Naloxone pretreatment did not block ketamine enantiomers' actions, but unexpectedly, increased fluoxetine' performance. Thus, while all three medications produced antidepressant-like effects in DRL 72-s, fluoxetine- and (S)- but not (R)- ketamine-induced time underestimation (the subject experiences the time as passing quickly). The potentiation of DRL performance of fluoxetine by naloxone was unexpected and warrants clinical studies.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 4
- (R)-(-)-Ketamine: The Promise of a Novel Treatment for Psychiatric and Neurological Disorders. International Journal of Molecular Sciences June 20, 2024
- Clinical pharmacological innovation in the treatment of depression. Expert Review of Clinical Pharmacology April 1, 2023
- Acute but not long-lasting antidepressant-like effect of psilocybin in differential reinforcement of low-rate 72 schedule in rats Journal of Psychopharmacology October 16, 2023
- Effects of ketamine enantiomers on morphine and THC subjective effects in rats. Journal of Psychopharmacology December 26, 2025
Cites 17
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Translational Psychiatry September 1, 2015
- Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism American Journal of Psychiatry August 29, 2018
- Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective Psychiatry and Clinical Neurosciences June 19, 2019
- Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability Molecular Psychiatry April 15, 2021
and 12 more in the library