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

TY - JOUR

T1 - Positive modulation of glutamatergic receptors potentiates the suppressive effects of antipsychotics on conditioned avoidance responding in rats

AU - Olsen, Christina Kurre

AU - Kreilgaard, Mads

AU - Didriksen, Michael

PY - 2006/6

Y1 - 2006/6

N2 - 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 alpha-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.

AB - 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 alpha-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.

KW - Animals

KW - Antipsychotic Agents

KW - Avoidance Learning

KW - Benzodiazepines

KW - Clozapine

KW - Conditioning (Psychology)

KW - Dioxoles

KW - Drug Synergism

KW - Isoxazoles

KW - Male

KW - Piperidines

KW - Pyrimidines

KW - Rats

KW - Rats, Wistar

KW - Receptors, AMPA

KW - Risperidone

KW - Serine

KW - Stereoisomerism

U2 - 10.1016/j.pbb.2006.05.006

DO - 10.1016/j.pbb.2006.05.006

M3 - Journal article

C2 - 16782180

SN - 0091-3057

VL - 84

SP - 259

EP - 265

JO - Pharmacology, Biochemistry and Behavior

JF - Pharmacology, Biochemistry and Behavior

IS - 2

ER -