Abstract
Glutamatergic system is implicated in pathogenesis of schizophrenia (Glutamate hypothesis) and stimulants for NMDA receptor glycine-binding sites are expected as novel medications for schizophrenia, especially for negative symptoms and cognitive impairments. However, the actions of NMDA receptor glycine-binding site agonists in modulating antipsychotic-induced EPS remain to be clarified. In this study, we examined the effects of the glycine-site agonists of NMDA receptors, D-cycloserine, D-serine and glycine on haloperidol-induced EPS (i.e., bradykinesia and catalepsy) in rodents. NMDA receptor glycine-binding site agonist, D-cycloserine (3–30 mg/kg, i.p.) significantly improved haloperidol (1 mg/kg, i.p.)-induced bradykinesia in a dose-dependent manner. D-serine (100–1000 mg/kg, i.p.) also reduced haloperidol-induced bradykinesia, but glycine (30–300 mg/kg, i.p.) did not. Attenuation of haloperidol-induced bradykinesia by D-cycloserine was reversed by the NMDA antagonist MK-801 or the NOS inhibitor L-NAME. In addition, microinjection of D-cycloserine (10 μg/μL/side) into substantia nigra or dorsolateral striatum, both significantly attenuated the EPS induction. The present results indicates that activation of glycine-binding sites of NMDA receptors alleviates the antipsychotic-induced EPS, implying that the glycine-binding site agonists of NMDA receptors, like D-cycloserine, provide benefits not only for the efficacy, but also in terms of EPS induction in the treatment of schizophrenia.