Development of glutamatergic antipsychotics requires efficient synaptic glutamatergic transmission while preventing NMDA receptor down-regulation and overactivation of extrasynaptic transmission.
BACKGROUND AND PURPOSE Clozapine and d-cycloserine improve negative symptoms of treatment-resistant schizophrenia, whereas combined administration of d-cycloserine plus clozapine aggravates them. However, the underlying mechanisms of these inconsistent effects remain unclear. EXPERIMENTAL APPROACH Effects of chronic administration of MK-801 (0.1 mg·kg-1·day-1), d-cycloserine (2 mg·kg-1·day-1), clozapine (5 mg·kg-1·day-1) and memantine (10 mg·kg-1·day-1) for 14 days on sucrose preference, GluN2A/GluN2B expression and basal and N-methyl-d-aspartate (NMDA)-evoked releases of l-glutamate/d-serine in the orbitofrontal cortex of male rats were determined. KEY RESULTS Chronic MK-801 administration decreased sucrose preference, GluN2A/GluN2B expression and NMDA-evoked release but increased basal extracellular l-glutamate/d-serine levels in the orbitofrontal cortex. Chronic administration of clozapine or d-cycloserine restored MK-801-induced sucrose preference impairments and NMDA-evoked release but left unaffected basal extracellular levels or GluN2A/GluN2B expression. Conversely, combined administration of clozapine + d-cycloserine further enhanced the MK-801-induced sucrose preference impairments, NMDA-evoked releases and GluN2A/GluN2B expressions and the increasing basal extracellular levels. Adding memantine to MK-801 + clozapine or MK-801 + clozapine + d-cycloserine reversed the sucrose preference, NMDA-evoked release and GluN2A/GluN2B expressions and the increasing basal extracellular levels. Tachyphylactic dose of d-cycloserine (25 mg·kg-1·day-1) decreased GluN2A/GluN2B expression, which was antagonised by the glycine-binding-site inhibitor MDL29951(10 mg·kg-1·day-1). Clozapine suppressed PP2A signalling. Chronic monotherapy with d-cycloserine or PP2A inhibitor LB-100 (1.5 mg·kg-1·day-1) left unaffected GluN2A/GluN2B expression, whereas their combined administration down-regulated them. CONCLUSION AND IMPLICATIONS These results suggest that potentiation of the NMDA receptor is involved in improving negative symptoms, but down-regulating NMDA receptor and enhanced extrasynaptic-NMDA receptor conversely contribute to the aggravation of negative symptoms.