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Vol. 293, Issue 1, 8-14, April 2000
Departments of Psychiatry (G.E.D., S.M., J.N.L., J.A.L.) and
Pharmacology (J.A.L.), and UNC Neuroscience Center (G.E.D., J.A.L.),
School of Medicine, University of North Carolina, Chapel Hill, North
Carolina
The ability of subanesthetic doses of
N-methyl-D-aspartate (NMDA)
antagonists to induce positive, negative, and cognitive schizophrenia-like symptoms suggests that reduced NMDA receptor function may contribute to the pathophysiology of schizophrenia. An
increasing body of evidence indicates that antipsychotic drugs, especially those with "atypical" properties, can antagonize the effects of NMDA antagonists in a variety of experimental paradigms. We
demonstrated previously that clozapine, the prototype of atypical antipsychotics, but not haloperidol, the typical antipsychotic, blocked
ketamine-induced alterations in brain metabolism. In this study,
effects of clozapine were compared with two of the newer atypical
antipsychotic drugs, risperidone and olanzapine, on ketamine-induced alterations in regional [14C]2-deoxyglucose (2-DG)
uptake. A subanesthetic dose of ketamine (25 mg/kg) induced robust
increases in 2-DG uptake in limbic cortical regions, hippocampal
formation, nucleus accumbens, and basolateral amygdala. Pretreatment of
rats with risperidone (0.3 mg/kg) before ketamine administration did
not alter the effects of ketamine. These data suggest that novel
pharmacological properties may contribute to the effects of clozapine
in this model, in addition to the well characterized actions at
D2 and 5HT2A receptors. In contrast to the
results with risperidone, olanzapine blocked ketamine-induced increases
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
expected if D2 and 5HT2 receptor blocking
properties of the drug were solely responsible for its action. The
results suggest that the ketamine challenge 2-DG paradigm may be a
useful model to identify antipsychotic drugs with atypical
characteristics and to explore mechanisms of atypical antipsychotic action.
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