Comparison of the effects of clozapine, risperidone, and olanzapine on ketamine-induced alterations in regional brain metabolism

The ability of subanesthetic doses of N-methyl-D-aspartate (NMDA) antagonis ts to induce positive, negative, and cognitive schizophrenia-like symptoms suggests that reduced NMDA receptor function may contribute to the pathophy siology of schizophrenia. An increasing body of evidence indicates that ant ipsychotic drugs, especially those with "atypical" properties, can antagoni ze the effects of NMDA antagonists in a variety of experimental paradigms. We demonstrated previously that clozapine, the prototype of atypical antips ychotics, but not haloperidol, the typical antipsychotic, blocked ketamine- induced alterations in brain metabolism. In this study, effects of clozapin e were compared with two of the newer atypical antipsychotic drugs, risperi done and olanzapine, on ketamine-induced alterations in regional [C-14]2-de oxyglucose (2-DG) uptake. A subanesthetic dose of ketamine (25 mg/kg) induc ed robust increases in 2-DG uptake in limbic cortical regions, hippocampal formation, nucleus accumbens, and basolateral amygdala. Pretreatment of rat s with risperidone (0.3 mg/kg) before ketamine administration did not alter the effects of ketamine. These data suggest that novel pharmacological pro perties may contribute to the effects of clozapine in this model, in additi on to the well characterized actions at D-2 and 5HT(2A) receptors. In contr ast to the results with risperidone, olanzapine blocked ketamine-induced in creases in 2-DG uptake. However, a higher dose of olanzapine (10 mg/kg) was required to completely block the effects of ketamine than would be expecte d if D-2 and 5HT(2) receptor blocking properties of the drug were solely re sponsible for its action. The results suggest that the ketamine challenge 2 -DG paradigm may be a useful model to identify antipsychotic drugs with aty pical characteristics and to explore mechanisms of atypical antipsychotic a ction.