Comparison of the Effects of Clozapine, Risperidone, and Olanzapine on Ketamine-Induced Alterations in Regional Brain Metabolism 1 GARY E. DUNCAN, SEIYA MIYAMOTO, JEREMY N. LEIPZIG, and JEFFREY A. LIEBERMAN 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 Accepted for publication December 16, 1999 This paper is available online at http://www.jpet.org ABSTRACT 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 clo- zapine, the prototype of atypical antipsychotics, but not halo- peridol, the typical antipsychotic, blocked ketamine-induced alterations in brain metabolism. In this study, effects of cloza- pine were compared with two of the newer atypical antipsy- chotic drugs, risperidone and olanzapine, on ketamine-induced alterations in regional [ 14 C]2-deoxyglucose (2-DG) uptake. A subanesthetic dose of ketamine (25 mg/kg) induced robust increases in 2-DG uptake in limbic cortical regions, hippocam- pal formation, nucleus accumbens, and basolateral amygdala. Pretreatment of rats with risperidone (0.3 mg/kg) before ket- amine 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 D 2 and 5HT 2A 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 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 atypical characteristics and to explore mechanisms of atypical antipsychotic action. Discovery of the remarkable efficacy of clozapine for the treatment of schizophrenia fostered a new era of antipsy- chotic drug development and has encouraged new pathophys- iological theories of schizophrenia (for review, see Kinon and Lieberman, 1996). Clozapine is effective in patients who are resistant to treatment with typical antipsychotics and does not induce the extrapyramidal side effects (EPS) character- istic of these agents (for review, see Bradford et al., 1998). The weak D 2 receptor blocking properties of clozapine readily explain the virtual absence of EPS induced by the drug and also suggest a fundamentally different therapeutic mecha- nism of action in comparison with the typical antipsychotic agents (Kapur et al., 1999). Unfortunately, administration of clozapine is associated with other serious sides effects in some patients, including agranulocytosis and seizures, that impose substantial limitations on its use. Development of new antipsychotic drugs that have the beneficial properties of clozapine without inducing adverse side effects has been hampered due to insufficient under- standing of the mechanisms of action of clozapine. Clozapine has weak antagonistic actions at D 1 and D 2 dopamine recep- tors and more potent antagonistic actions at 5HT 2A , 5HT 2C , 5HT 6 , 5HT 7 ,  1 - and  2 -adrenergic, H 1 histamine, and M 1 muscarinic receptors (Kinon and Lieberman, 1996; Meltzer, 1996). In addition, clozapine has 5HT 1A receptor agonistic properties (Rollema et al., 1997). Whether any of these ac- tions of clozapine, alone or in combination, account for its therapeutic efficacy is uncertain. The rationale for development of the newer antipsychotic drugs, such as risperidone and olanzapine, and their classi- fication as atypical has been based predominantly on antag- onistic properties at 5HT 2A and D 2 receptors. However, it may be prudent to consider additional mechanisms of anti- psychotic drug action and strategies for drug discovery based on pathophysiological hypotheses of schizophrenia other Received for publication August 17, 1999. 1 This work was supported in part by Public Health Service research and center Grants MH-33127, MH-00537, HD-03110; Lilly Research Laboratories; and the Foundation of Hope. ABBREVIATIONS: EPS, extrapyramidal side effects; 2-DG, [ 14 C]2-deoxygluclose; PPI, prepulse inhibition; NMDA, N-methyl-D-aspartate; PCP, phencylidine. 0022-3565/00/2931-0008$03.00/0 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 293, No. 1 Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. JPET 293:8–14, 2000 8 at ASPET Journals on February 27, 2018 jpet.aspetjournals.org Downloaded from