The present study investigates the efficacy of a cholinesterase inhibitor, metrifonate, to desynchronize cortical EEG activity in muscarinic acetylcholine receptor antagonist (scopolamine 0.2 mg/kg, i.p.) treated and nucleus basalis (NB)-lesioned young rats and in aged rats. In young (10, 30 and 60 mg/kg, p.o.) and aged (3, 10, 30 and 60 mg/kg, p.o.) rats metrifonate suppressed spontaneously occurring immobility related high voltage spindling (HVS) activity. Scopolamine increased neocortical slow waves and 1-20 Hz amplitude values. Metrifonate (10, 30 and 100 mg/kg, p.o.) fully and THA (3 and 6 mg/kg, i.p.) partially restored normal EEG activity. Quisqualic acid NB lesions decreased frontal cortical choline acetyltransferase activity by 80 % and increased cortical EEG slow waves. Metrifonate (30 and 100 mg/kg, p.o.) and THA (3 and 6 mg/kg, i.p.) were not able to reverse NB lesion-induced EEG abnormality. These data suggest that metrifonate may enhance the activity of cholinergic synapses involved in the activation of cortical EEG waves and that a severe defect of presynaptic NB cholinergic fibers may block the therapeutic effects of metrifonate.