D-Serine and a glycine transporter inhibitor improve MK-801-induced cognitive deficits in a novel object recognition test in rats.
Compounds enhancing N-methyl-d-aspartate (NMDA) glutamate receptor function have been reported to improve cognitive deficits. Since cognitive deficits are considered to be the core symptom of schizophrenia, enhancing NMDA receptor function represents a promising approach to treating schizophrenia. In the present study, we investigated whether d-serine or a glycine transporter inhibitor N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine (NFPS), both of which enhance NMDA receptor function, could improve MK-801-induced cognitive deficits in rats, and compared their effects with those of the atypical antipsychotic clozapine and of the typical antipsychotic haloperidol. To assess cognitive function, we used a novel object recognition test in rats that measured spontaneous exploratory activity of a novel object when paired with a familiar object. We then evaluated the effects of the compounds on cognitive deficits induced by treatment with MK-801, the NMDA receptor antagonist. Pretreatment with clozapine (1, 5 mg/kg, i.p.) but not haloperidol (0.03, 0.1 mg/kg, i.p.) significantly improved MK-801-induced cognitive deficits. Pretreatment with D-serine at 800 mg/kg (i.p.) or NFPS (0.3, 1 mg/kg, i.p.) significantly improved MK-801-induced cognitive deficits under this test paradigm. These findings suggest that impaired preference for novel objects induced by MK-801 in the novel object recognition test could be a useful animal model for evaluating the efficacy of compounds targeting the cognitive deficits observed in schizophrenic patients. The results also suggest that enhancing NMDA receptor function is an effective way for treating the cognitive deficits associated with schizophrenia.
Karasawa
Jun-Ichi
J
Discovery Pharmacology, Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
Hashimoto
Kenji
K
Chaki
Shigeyuki
S
D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D016291:Dizocilpine Maleate; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D018697:Nootropic Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology*; D012521:Sarcosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D012694:Serine / Q000378:metabolism / Q000494:pharmacology*; D018709:Statistics, Nonparametric
D014150:Antipsychotic Agents; D050487:Glycine Plasma Membrane Transport Proteins; C435025:N-(3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)-3-(4'-phenylphenoxy)propyl)sarcosine; D018697:Nootropic Agents; D016194:Receptors, N-Methyl-D-Aspartate; C493266:Slc6a9 protein, rat; D012694:Serine; D016291:Dizocilpine Maleate; D003024:Clozapine; D006220:Haloperidol; D012521:Sarcosine