d-Serine and a glycine transporter-1 inhibitor enhance social memory in rats

Rationale Glutamatergic abnormalities are involved in the etiology of schizophrenia. Clinical evidence demonstrates that positive modulation of “glycine modulatory sites” on N -methyl- d -aspartic acid (NMDA) receptors improve cognitive deficits as well as positive and negative symptoms in schizophrenic patients. Objectives In the present study, we investigated the effects of positive modulation of glycine sites on the NMDA receptor using an agonist of the glycine modulatory site, d -serine, and a glycine transporter-1 inhibitor, ( R )-( N -[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl])sarcosine (NFPS). In particular, we focused on the effects on cognitive functioning using social recognition test in rats. We then compared these effects with those of an atypical antipsychotic clozapine and a typical antipsychotic haloperidol. Results Both d -serine and NFPS significantly enhanced social memory in naïve rats, as did clozapine, while the typical antipsychotic haloperidol was ineffective. A noncompetitive NMDA receptor antagonist, MK-801, significantly impaired social memory, which was significantly attenuated by pretreatment with clozapine, but not with haloperidol. Likewise, NFPS significantly improved MK-801-disrupted cognition in the social recognition test. None of these drugs affected social interaction time. Conclusions The present results show that stimulation of the glycine modulatory sites on the NMDA receptor either directly with d -serine or by blocking glycine transporter-1 enhances social memory and may be an effective approach for the treatment of the cognitive dysfunction observed in schizophrenic patients.