title: 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.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, 303 E Chicago Ave., 7-101, Chicago, IL 60611, USA.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Rajagopal
authors.affiliation: Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, 1801 Maple Ave., Suite 4300, Evanston, IL 60201, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Burgdorf
authors.affiliation: Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, 1801 Maple Ave., Suite 4300, Evanston, IL 60201, USA; Naurex Inc., 1801 Maple Ave., Suite 4300, Evanston, IL 60201, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Moskal
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, 303 E Chicago Ave., 7-101, Chicago, IL 60611, USA. Electronic address: h-meltzer@northwestern.edu.
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Meltzer
mesh_terms: D000818:Animals; D003071:Cognition / Q000187:drug effects; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage*; D007649:Ketamine; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000008:administration & dosage*; D010622:Phencyclidine; D021641:Recognition, Psychology / Q000502:physiology
chemical_list: D018691:Excitatory Amino Acid Antagonists; D009842:Oligopeptides; D007649:Ketamine; C507283:GLYX-13 peptide; D010622:Phencyclidine
keywords: Depression; GLYX-13; Ketamine; Novel object recognition; PCP; Rapastinel