Blunted brain metabolic response to ketamine in mice lacking D1A dopamine receptors

Seiya Miyamoto, Richard B. Mailman, Jeffrey A. Lieberman, Gary E. Duncan

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


The interaction of glutamatergic and dopamine neurotransmission is thought to have relevance to both the pathophysiology and pharmacotherapy of schizophrenia. For example, subanesthetic doses of the N-methyl-D-aspartate receptor (NMDA-R) antagonist ketamine induce schizophrenia-like behavioral effects in humans and both behavioral and brain metabolic activation in rodents. Blockade of NMDA-R results in dopamine release, and antipsychotic drugs that block dopamine neurotransmission decrease NMDA-R antagonist-induced behavioral activation. The involvement of dopamine receptors in brain metabolic activation induced by ketamine is, however, unknown. The present study used D1A knockout mice to determine the role of dopamine D1A receptors in the effects of subanesthetic doses of ketamine on both behavioral responses and on alterations in regional [14C]2-deoxyglucose (2-DG) uptake. There was less ketamine-induced behavioral activation in D1A knockout mice than in wild-type mice. In wild-type mice, ketamine (30 mg/kg) induced dramatic increases in 2-DG uptake in limbic cortical regions, hippocampal formation, nucleus accumbens, basolateral amygdala, and caudal parts of the substantia nigra pars reticulata. D1A knockout mice exhibited blunted metabolic activation in response to ketamine in a neuroanatomically specific manner. The selective D1 antagonist, SCH23390 (0.3 mg/kg), inhibited both ketamine-induced brain metabolic activation and behavioral responses in the wild-type mice, with a similar neuroanatomical specificity observed in the D1A knockout mice. Thus, the neuroanatomically selective role that D1A receptors play in ketamine-induced behavior and regional brain metabolic activation in mice provides a useful model for further studies of how the D1A receptor function may be altered in schizophrenia.

Original languageEnglish (US)
Pages (from-to)167-180
Number of pages14
JournalBrain research
Issue number2
StatePublished - Mar 16 2001

All Science Journal Classification (ASJC) codes

  • General Neuroscience
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology


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