Although the pathophysiology of schizophrenia remains unclear, behavioral effects in humans induced by N-methyl-D-aspartate (NMDA) antagonists, such as ketamine, provide direction for formulating new pharmacologic models of the illness. The purpose of the present study was to clarify the roles of NMDA receptor antagonism, as well as dopamine-releasing properties of ketamine, in regional brain metabolic activity and behavioral responses in mice. The effects of acute administration of ketamine (30 mg/kg, i.p.) were compared with those of the more selective non-competitive NMDA antagonist MK-801 (0.3 and 0.5 mg/kg, i.p.), and amphetamine (4 mg/kg, i.p.) on regional brain [14C]-2-deoxyglucose (2-DG) uptake, by using a high resolution autoradiographic technique in the freely moving mice. Both ketamine and MK-801 induced substantial and similar neuroanatomically selective alterations in regional 2-DG uptake. Remarkable increases in 2-DG uptake in response to the NMDA antagonists were seen in limbic cortical regions, hippocampal formation, nucleus accumbens, select thalamic nuclei, and basolateral amygdala. The behavior of mice given amphetamine was similar to that of mice given MK-801. However, the brain activity patterns induced by amphetamine were distinctly different from those observed after ketamine and MK-801 treatment. These results suggest that generalized behavioral activation and increased dopamine release are insufficient to account for the ketamine-induced alterations in regional brain metabolism, and that the effects of ketamine on 2-DG uptake are likely related to a reduction in NMDA receptor function. The data also suggest that ketamine-induced changes in 2-DG uptake may provide a useful paradigm for translational research to better understand the pathophysiology of schizophrenia.