Subanesthetic doses of NMDA receptor antagonists induce positive, negative and cognitive schizophrenia-like symptoms in healthy humans and precipitate psychotic reactions in stabilized schizophrenic patients. These findings suggest that defining neurobiologic effects induced by NMDA antagonists could guide the formulation of experimental models relevant to the pathophysiology of schizophrenia and antipsychotic drug action. Accordingly, the effects of subanesthetic doses of the non-competitive NMDA antagonists ketamine and MK-801 were examined on regional brain [14C]-2-deoxyglucose (2-DG) uptake in rats. The effects of these drugs were compared to those of amphetamine, in order to assess the potential role of generalized behavioral arousal, motor activity and dopamine release in brain metabolic responses to the NMDA antagonists. Subanesthetic doses of MK-801 and ketamine induced identical alterations in patterns of 2-DG uptake. The most pronounced increases in 2-DG for both NMDA antagonists were in the hippocampal formation and limbic cortical regions. By contrast, amphetamine treatment did not increase 2-DG uptake in these regions. In isocortical regions, ketamine and MK-801 reduced uptake in layers 3 and 4, creating a striking shift in the laminar pattern of 2-DG uptake in comparison to control conditions. After amphetamine, the fundamental laminar pattern of isocortical labeling was similar to saline-treated rats. Administration of ketamine and MK-801 decreased 2-DG uptake in the medial geniculate and inferior colliculus, whereas amphetamine tended to increase uptake in these regions. Since ketamine induced similar effects on regional 2-DG uptake as observed for the selective antagonists MK-801, the effects of ketamine are likely related to NMDA antagonistic properties of the drug. The distinct differences in brain 2-DG uptake induced by amphetamine and NMDA antagonists indicate that generalized behavioral arousal, and increased locomotor activity mediated by dopamine release, are not sufficient to account for the alterations in brain metabolic patterns induced by ketamine and MK-801. Thus, the dramatic alteration in regional 2-DG uptake induced by ketamine and MK-801 reflects a state selectively induced by reduced NMDA receptor function.