Electroencephalographic activation by fluoxetine in rats: role of 5-HT(1A) receptors and enhancement of concurrent acetylcholinesterase inhibitor treatment.
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 20 mg/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-HT(1A) 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-HT(1A) 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.
Dringenberg
Hans C
HC
Department of Psychology, Queen's University, Kingston, Ontario, Canada K7L 3N6. dringenb@psych.queensu.ca
Diavolitsis
Peter
P
D000513:Alpha Rhythm / Q000187:drug effects; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003625:Data Collection; D004569:Electroencephalography / Q000187:drug effects*; D005473:Fluoxetine / Q000494:pharmacology*; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D012110:Reserpine / Q000494:pharmacology; D012601:Scopolamine / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013619:Tacrine / Q000494:pharmacology
D014150:Antipsychotic Agents; D002800:Cholinesterase Inhibitors; D005473:Fluoxetine; D018727:Muscarinic Antagonists; D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012110:Reserpine; D012601:Scopolamine; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D013619:Tacrine; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide