GLYX-13 (rapastinel) ameliorates subchronic phencyclidine- and ketamine-induced declarative memory deficits in mice.
Lakshmi Rajagopal, Jeffrey S Burgdorf, Joseph R Moskal, Herbert Y. Meltzer
Behavioural Brain Research February 15, 2016 DOI: 10.1016/j.bbr.2015.10.060 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Male C57BL/6J mice |
| Interventions | Ketamine Phencyclidine (PCP) Lurasidone |
| Dose | Ketamine 30 mg/kg i.p.; rapastinel 1.0 mg/kg i.v. (also tested at 0.3 mg/kg i.v.) |
| Measures | Novel object recognition (NOR) |
| Topics | Depression Ketamine Esketamine |
| Keywords | Glyx-13 Novel object recognition Pcp Rapastinel |
| Key points | Rapastinel (1.0 mg/kg intravenously) did not impair novel object recognition in mice, prevented acute ketamine-induced memory deficits, and reversed deficits from subchronic ketamine or phencyclidine, while 0.3 mg/kg did not reverse them. The authors argue rapastinel differs from ketamine in lacking declarative memory-impairing effects and may have add-on potential with antipsychotic/antidepressant drugs, though they note clinical translation remains to be tested. |
Abstract
GLYX-13 (rapastinel), a tetrapeptide (Thr-Pro-Pro-Thr-amide), has been reported to have fast acting antidepressant properties in man based upon its N-methyl-D-aspartate receptor (NMDAR) glycine site functional partial agonism. Ketamine, a non-competitive NMDAR antagonist, also reported to have fast acting antidepressant properties, produces cognitive impairment in rodents and man, whereas rapastinel has been reported to have cognitive enhancing properties in rodents, without impairing cognition in man, albeit clinical testing has been limited. The goal of this study was to compare the cognitive impairing effects of rapastinel and ketamine in novel object recognition (NOR), a measure of declarative memory, in male C57BL/6J mice treated with phencyclidine (PCP), another NMDAR noncompetitive antagonist known to severely impair cognition, in both rodents and man. C57BL/6J mice given a single dose or subchronic ketamine (30 mg/kg.i.p.) showed acute or persistent deficits in NOR, respectively. Acute i.v. rapastinel (1.0 mg/kg), did not induce NOR deficit. Pre-treatment with rapastinel significantly prevented acute ketamine-induced NOR deficit. Rapastinel (1.0 mg/kg, but not 0.3 mg/kg, iv) significantly reversed both subchronic ketamine- and subchronic PCP-induced NOR deficits. Rapastinel also potentiated the atypical antipsychotic drug with antidepressant properties, lurasidone, to restore NOR in subchronic ketamine-treated mice. These findings indicate that rapastinel, unlike ketamine, does not induce a declarative memory deficit in mice, and can prevent or reverse the ketamine-induced NOR deficit. Further study is required to determine if these differences translate during clinical use of ketamine and rapastinel as fast acting antidepressant drugs and if rapastinel could have non-ionotropic effects as an add-on therapy with antipsychotic/antidepressant medications.
Comparable studies
Other preclinical and animal studies on ketamine for depression, most cited first.
Citations in the library
Cited by 12
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- Molecular Pharmacology and Neurobiology of Rapid-Acting Antidepressants The Annual Review of Pharmacology and Toxicology October 9, 2018
- Psychosis: The Utility of Ketamine as a Pharmacological Model of Psychotic-like Symptoms in Rodents: A Review of Dosage Regimens Biology January 25, 2026
- NMDA Receptor Glycine Binding Site Modulators for Prevention and Treatment of Ketamine Use Disorder. Pharmaceuticals May 30, 2023
- Repeated administration of rapastinel produces exceptionally prolonged rescue of memory deficits in phencyclidine-treated mice. Behavioural Brain Research August 26, 2022
and 7 more in the library
Cites 8
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- NMDA receptor regulation of memory and behavior in humans Hippocampus October 1, 2001
- Ketamine as a promising prototype for a new generation of rapid‐acting antidepressants Annals of the New York Academy of Sciences February 27, 2015
- Subchronic phencyclidine treatment in adult mice increases GABAergic transmission and LTP threshold in the hippocampus. Neuropharmacology January 2016
- Nicotine improves working memory span capacity in rats following sub-chronic ketamine exposure. Neuropsychopharmacology December 2011
and 3 more in the library