Repeated administration of rapastinel produces exceptionally prolonged rescue of memory deficits in phencyclidine-treated mice.
Lakshmi Rajagopal, Mei Huang, Wenqi He, Chelsea Ryan, Ahmad Elzokaky, Pradeep Banerjee, Herbert Y. Meltzer
Behavioural Brain Research August 26, 2022 DOI: 10.1016/j.bbr.2022.113964 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Subchronic PCP-treated mice |
| Interventions | Rapastinel Ketamine Phencyclidine (PCP) |
| Dose | Rapastinel 1 or 3 mg/kg; rapastinel 1 mg/kg twice daily; ketamine 30 mg/kg; PCP (dose not stated) |
| Duration | Rapastinel given twice daily for 3 or 5 days, with NOR restoration lasting at least 9 and 10 weeks, respectively; single-dose testing 30 min before NOR or ORL |
| Measures | Novel object recognition (NOR), operant reversal learning (ORL) |
| Topics | Ketamine |
| Keywords | Antidepressant Novel object recognition Operant reversal learning Phencyclidine Rapastinel |
| Key points | Single doses of rapastinel (1 or 3 mg/kg) transiently rescued NOR and ORL deficits in subchronic PCP mice in an mTOR-dependent manner, while 1 mg/kg twice daily for 3 or 5 days restored NOR for at least 9 and 10 weeks, indicating neuroplastic effects. Both rapastinel and ketamine moderately increased cortical dopamine, norepinephrine, and serotonin efflux, but only ketamine increased glutamate efflux, which the authors suggest may underlie their contrasting cognitive effects. |
Abstract
Rapastinel, a positive N-methyl-D-aspartate receptor (NMDAR) modulator with rapid-acting antidepressant properties, rescues memory deficits in rodents. We have previously reported that a single intravenous dose of rapastinel, significantly, but only transiently, prevented and rescued deficits in the novel object recognition (NOR) test, a measure of episodic memory, produced by acute or subchronic administration of the NMDAR antagonists, phencyclidine (PCP) and ketamine. Here, we tested the ability of single and multiple subcutaneous doses per day of rapastinel to restore NOR and operant reversal learning (ORL) deficits in subchronic PCP-treated mice. Rapastinel, 1 or 3 mg/kg, administered subcutaneously, 30 min before NOR or ORL testing, respectively, transiently rescued both deficits in subchronic PCP mice. This effect of rapastinel on NOR and ORL was mammalian target of rapamycin (mTOR)-dependent. Most importantly, 1 mg/kg rapastinel given twice daily for 3 or 5 days, but not 1 day, restored NOR for at least 9 and 10 weeks, respectively, which is an indication of neuroplastic effects on learning and memory. Both rapastinel (3 mg/kg) and ketamine (30 mg/kg), moderately increased the efflux of dopamine, norepinephrine, and serotonin in medial prefrontal cortex; however, only ketamine increased cortical glutamate efflux. This observation was likely the basis for the contrasting effects of the two drugs on cognition.
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 2
- Emerging Medications for Treatment-Resistant Depression: A Review with Perspective on Mechanisms and Challenges Brain Sciences February 6, 2025
- Ibogalogs improve spatial and recognition memory in rodents through a mechanism involving 5-HT2A receptor activation-enhanced NMDA receptor activity in hippocampal pyramidal CA1 neurons Biomedicine & Pharmacotherapy November 13, 2025
Cites 14
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders JAMA Psychiatry March 1, 2017
- Reviewing the ketamine model for schizophrenia Journal of Psychopharmacology November 20, 2013
- Glutamatergic Deficits in Schizophrenia – Biomarkers and Pharmacological Interventions within the Ketamine Model Current Pharmaceutical Biotechnology June 21, 2018
- TPA-023 attenuates subchronic phencyclidine-induced declarative and reversal learning deficits via GABAA receptor agonist mechanism: possible therapeutic target for cognitive deficit in schizophrenia. Neuropsychopharmacology November 2018
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