In this study we have used electrophysiological and metabolic markers to investigate the effects of competitive and non-competitive NMDA antagonists in rats after central or peripheral administration. The non-competitive antagonist, MK-801, induced dose-dependent suppression of rat hippocampal EEG energy both after intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) application. Similar effects were observed after i.p. and i.c.v. application of the competitive antagonist, DL-CPP-ene. Whereas the MK-801 was more potent after i.p. application, DL-CPP-ene was more potent after i.c.v. administration. Intracerebroventricular administration of MK-801 and DL-CPP-ene resulted in similar changes in the pattern of local cerebral glucose utilization in the olfactory tubercle and regions of the limbic system such as the anteroventral thalamus, hippocampus and entorhinal cortex. Intravenous (i.v.) administration of MK-801 induced increases in glucose metabolism similar to those observed after i.c.v. application. In contrast, i.v. administration of DL-CPP-ene induced only small decreases of glucose utilization in several regions of the central sensory system. Thus the blockade of glutamatergic (NMDA) transmission results in decreased hippocampal EEG activity which is paralleled by increased metabolic activity in this area. We conclude from EEG recordings and [14C]2-deoxyglucose uptake experiments that both non-competitive and competitive NMDA antagonists produce the same pattern of alterations after i.c.v. administration. Apparent differences in efficacy after peripheral administration may be largely due to differences in bioavailability.