GLYX-13 (rapastinel) ameliorates subchronic phencyclidine- and ketamine-induced declarative memory deficits in mice

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.

Keywords: Depression; GLYX-13; Ketamine; Novel object recognition; PCP; Rapastinel.

Fig. 1

The effect of saline (Sal; 0.9%; iv), acute rapastinel (rap; 1.0 mg/kg; iv), acute ketamine (ket; 30 mg/kg; ip); rap + ket (1.0 mg/kg + 30 mg/kg) in an NOR task in male C57BL/6J mice. Data are expressed as mean ± S.E.M. (N = 7–10 per group). DI, ***P < 0.001; significant reduction in DI compared to sal; ^###P < 0.001; significant reduction in DI compared to rap + Sal; $$$P<0.001; significant increase in DI compared to ket + sal.

Fig. 2

The effect of subchronic sal (0.9%), subchronic PCP and subchronic ket (10 and 30 mg/kg; ip; bid; 7 days; 7 days washout); subchronic PCP + rap(1.0 mg/kg), and subchronic ket + rap(1.0 mg/kg) in an NOR task in male C57BL/6J mice. Data are expressed as mean ± S.E.M. (N = 7–10 per group). DI, *P < 0.05; **P < 0.01; significant reduction in DI compared to Sal treatment. ^###P < 0.001; significant increase in DI in subchronic PCP- and subchronic ket-treated mice given rap (1.0 mg/kg) compared to subchronic PCP + Sal or subchronic ket + Sal.

Fig. 3

The effect of subchronic Sal (0.9%), subchronic ket (30 mg/kg), subchronic ket + rap(0.3 mg/kg; sub-effective dose), subchronic ket + lurasidone (0.1 mg/kg; lur; sub-effective dose), subchronic ket + sub-effective dose rap + sub-effective dose lur in an NOR task in male C57BL/6J mice. Data are expressed as mean ± S.E.M. (N = 8–10 per group). DI, ***P < 0.001; significant reduction in DI compared to Sal-treated mice. ^###P < 0.001: Significant increase in DI compared to subchronic ket + Sal; subchronic ket + sub-effective dose rap; subchronic ket + sub-effective dose lur.