Differential effects of clozapine and haloperidol on ketamine-induced brain metabolic activation

Gary E. Duncan, Jeremy N. Leipzig, Richard Mailman, Jeffery A. Lieberman

Research output: Contribution to journalArticle

104 Citations (Scopus)

Abstract

Subanesthetic doses of N-methyl-D-aspartate (NMDA) receptor antagonists such as ketamine and phencyclidine precipitate psychotic symptoms in schizophrenic patients. In addition, these drugs induce a constellation of behavioral effects in healthy individuals that resemble positive, negative, and cognitive symptoms of schizophrenia. Such findings have led to the hypothesis that decreases in function mediated by NMDA receptors may be a predisposing, or even causative, factor in schizophrenia. The present study examined the effects of the representative atypical (clozapine) and typical (haloperidol) antipsychotic drugs on ketamine- induced increases in [14C]- 2-deoxyglucose (2-DG) uptake in the rat brain. As previously demonstrated, administration of subanesthetic doses of ketamine increased 2-DG uptake in specific brain regions, including medial prefrontal cortex, retrosplenial cortex, hippocampus, nucleus accumbens, basolateral amygdala, and anterior ventral thalamic nucleus. Pretreatment of rats with 5 or 10 mg/kg clozapine alone produced minimal or no change in 2-DG uptake, yet clozapine completely blocked ketamine-induced changes in 2-DG uptake in all brain regions studied. In striking contrast, a dose of haloperidol (0.5 mg/kg) that produces a substantial cataleptic response, potentiated, rather than blocked, ketamine- induced activation of 2-DG uptake. These results demonstrate, in a model with potential relevance to schizophrenia, a striking neurobiological difference between the actions of prototypical typical and atypical antipsychotic drugs. The dramatic blockade by clozapine of ketamine-induced brain metabolic activation suggests that antagonism of the consequences of reduced NMDA receptor function could contribute to the superior therapeutic effects of this atypical antipsychotic agent. The results also suggest that this model of ketamine-induced alterations in 2-DG uptake may be extremely useful for understanding the complex neural mechanisms of atypical antipsychotic drug action.

Original languageEnglish (US)
Pages (from-to)65-75
Number of pages11
JournalBrain research
Volume812
Issue number1-2
DOIs
StatePublished - Nov 23 1998

Fingerprint

Clozapine
Ketamine
Haloperidol
Deoxyglucose
Brain
Antipsychotic Agents
N-Methyl-D-Aspartate Receptors
Schizophrenia
Ventral Thalamic Nuclei
Phencyclidine
Neurobehavioral Manifestations
Nucleus Accumbens
Therapeutic Uses
Metabolic Activation
Prefrontal Cortex
Hippocampus
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

Cite this

Duncan, Gary E. ; Leipzig, Jeremy N. ; Mailman, Richard ; Lieberman, Jeffery A. / Differential effects of clozapine and haloperidol on ketamine-induced brain metabolic activation. In: Brain research. 1998 ; Vol. 812, No. 1-2. pp. 65-75.
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Differential effects of clozapine and haloperidol on ketamine-induced brain metabolic activation. / Duncan, Gary E.; Leipzig, Jeremy N.; Mailman, Richard; Lieberman, Jeffery A.

In: Brain research, Vol. 812, No. 1-2, 23.11.1998, p. 65-75.

Research output: Contribution to journalArticle

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