Repeated administration of rapastinel produces exceptionally prolonged rescue of memory deficits in phencyclidine-treated mice

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.