Positive modulation of glutamatergic receptors potentiates the suppressive effects of antipsychotics on conditioned avoidance responding in rats

Non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist administration induces a syndrome indistinguishable from schizophrenia including positive and negative symptoms and cognitive deficits. Concordantly, augmentation of the NMDA receptor function by glycine-site agonists such as d-serine and d-cycloserine has been reported to improve negative symptoms and some cognitive deficits in schizophrenia patients when added to conventional antipsychotic treatment, although they appear less effective when combined with clozapine specifically. In contrast, administration of the AMPAkine CX-516 (which positively modulate the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor) as an adjuvant to clozapine, has been shown to exert some beneficial action on the negative symptoms and cognitive deficits in schizophrenia. In the rat, selective suppression of conditioned avoidance response (CAR) behaviour has been widely reported to be a test with high predictive validity for antipsychotic efficacy. We found that d-serine and CX-516, at doses ineffective by themselves, significantly potentiated the suppression of CAR induced by threshold doses of risperidone (0.16 mg/kg, s.c.), olanzapine (0.63 mg/kg, s.c.) and clozapine (1.3 mg/kg, s.c.) without causing additional motor disturbances. Thus, the adjunct enhancement of NMDA or AMPA receptor function observed clinically, appears reflected in the present rat CAR study. Consequently, our data lend further support to the potential use of the CAR test in the investigation of augmentation strategies involving the addition of non-dopaminergic target compounds to existing atypical antipsychotics.