Comparison of brain metabolic activity patterns induced by ketamine, MK-801 and amphetamine in rats: support for NMDA receptor involvement in responses to subanesthetic dose of ketamine

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 s uggest that defining neurobiologic effects induced by NMDA antagonists coul d guide the formulation of experimental models relevant to the pathophysiol ogy of schizophrenia and antipsychotic drug action. Accordingly, the effect s of subanesthetic doses of the non-competitive NMDA antagonists ketamine a nd MK-801 were examined on regional brain [C-14]-2-deoxyglucose (2-DG) upta ke in rats. The effects of these drugs were compared to those of amphetamin e, in order to assess the potential role of generalized behavioral arousal, motor activity and dopamine release in brain metabolic responses to the NM DA antagonists. Subanesthetic doses of MK-801 and ketamine induced identica l 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 reduc ed uptake in layers 3 and 3, creating a striking shift in the laminar patte rn of 2-DG uptake in comparison to Control conditions. After amphetamine, t he fundamental laminar pattern of isocortical labeling was similar to salin e-treated rats. Administration of ketamine and MK-801 decreased 2-DG uptake in the medial geniculate and inferior colliculus, whereas amphetamine tend ed to increase uptake in these regions. Since ketamine induced similar effe cts on regional 2-DG uptake as observed for the selective antagonists MK-80 1, the effects of ketamine are likely related to NMDA antagonistic properti es of the drug. The distinct differences in brain 2-DG uptake induced by am phetamine and NMDA antagonists indicate that generalized behavioral arousal , and increased locomotor activity mediated by dopamine release, are not su fficient to account for the alterations in brain metabolic patterns induced by ketamine and MK-801. Thus, the dramatic alteration in regional 2-DG upt ake induced by ketamine and, MK-801 reflects a state selectively induced by reduced NMDA receptor function. (C) 1999 Elsevier Science B.V. All rights reserved.