DOI: 10.1111/bph.70646 ISSN: 0007-1188
Development of glutamatergic antipsychotics requires efficient synaptic glutamatergic transmission while preventing NMDA receptor down‐regulation and overactivation of extrasynaptic transmission
Ruri Okubo, Tomoka Oka, Eishi Motomura, Motohiro OkadaBackground 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.