Considerable evidence indicates that both cholinergic (ACh) and serotonergic (5-HT) inputs to the neocortex play a direct role in maintaining the activated state of the electroencephalogram (EEG). Here, we investigated frequency-specific EEG effects of the 5-HT re-uptake inhibitor fluoxetine (10 and 20mg/kg) to restore EEG activation abolished by combined treatment with the monoamine depletor reserpine (10 mg/kg) and the muscarinic antagonist scopolamine (1 mg/kg). Fluoxetine alone was ineffective in reversing EEG slowing produced by reserpine–scopolamine administration. However, fluoxetine suppressed EEG synchronization in the alpha (8–12 Hz) band when administered concurrently with the 5-HT1A receptor antagonist WAY 100635 (0.5 mg/kg). Further, fluoxetine, with and without WAY 100635, markedly potentiated the effectiveness of the acetylcholinesterase (AChE) inhibitor tacrine (5 mg/kg) to restore EEG activation between 4–30 Hz. These data indicate that 5-HT uptake inhibition and concurrent 5-HT1A receptor blockade produce a limited normalization of the cortical EEG after monoaminergic–cholinergic blockade. However, fluoxetine strongly potentiates the effectiveness of tacrine to restore EEG activation. Inhibitors of AChE are used to delay cognitive decline and EEG slowing in patients with Alzheimer's disease. We suggest that doses of AChE inhibitors required for these effects can be reduced by concurrent 5-HT stimulation.