Abstract
The fact that chronic administration of typical and atypical antipsychotic drugs is required for optimal therapeutic response suggests that drug-induced adaptive neurochemical changes contribute to their mechanism of action. In the present study, the effects of chronic and acute haloperidol and olanzapine were compared on ketamine-induced activation of select brain regions, as reflected by altered regional 14C-2-deoxyglucose (2-DG) uptake. Rats were injected once daily with haloperidol (1 mg/kg) or olanzapine (10 mg/kg) for 21 days, and 20 to 24 h after the final injection was challenged with saline or ketamine (25 mg/kg). The washout period was used to test the effects of chronic drug treatment without the influence of acute drug administration. In vehicle-treated rats, ketamine increased 2-DG uptake in select brain regions, including medial prefrontal cortex, nucleus accumbens, caudate putamen, stratum lacunosum-moleculare of hippocampus, and basolateral nucleus of the amygdala. This selective activation was attenuated by prior chronic treatment with both haloperidol and olanzapine. After acute treatment, olanzapine, but not haloperidol, blocked the ketamine-induced activation of 2-DG uptake. These data suggest that both haloperidol and olanzapine can induce adaptive responses that counteract effects of ketamine. However, the differences observed in the acute effects of the two drugs in the ketamine challenge model suggest that different mechanisms could be responsible for their common chronic action of attenuating ketamine-induced brain metabolic activation.
Footnotes
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This work was supported in part by the University of North Carolina Silvio O. Conte Center for the Neuroscience of Mental Disorders (MH064065) (J.L.), Lilly Research Laboratories (G.D.), and the Foundation of Hope Raleigh North Carolina (J.L., G.D.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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DOI: 10.1124/jpet.102.048140.
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ABBREVIATIONS: NMDA, N-methyl-d-aspartic acid; 2-DG, 14C-2-deoxyglucose; PCP, phencyclidine; PPI, prepulse inhibition; ANOVA, analysis of variance.
- Received December 14, 2002.
- Accepted February 18, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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