Synergistic effects of acetylcholinesterase (AChE) inhibition and NMDA receptor modulation on acetylcholine levels

Abstract

AChE inhibitors increase brain acetylcholine (ACh) levels by preventing the breakdown of ACh. Systemic administration of NMDA or NMDA receptor antagonists does not alter AChE activity. However, brain ACh levels are decreased or increased by NMDA or NMDA antagonists, respectively, by altering the glutamatergic regulation of ACh release, a mechanism distinct from AChE inhibition. In the present study, the effects of an NMDA receptor antagonist (memantine) and an AChE inhibitor (donepezil) on hippocampal ACh levels were determined in anesthetized rats using a microdialysis technique. Donepezil (0.25, 0.5 & 1.0 mg/kg, i.p.) dose-dependently increased the basal ACh level (+ 50%–100%). Memantine (2.5, 5 & 10 mg/kg, i.p.) also dose-dependently increased the basal ACh levels (+110%–250%) in the rat hippocampus. The concomitant administration of donepezil (0.5 mg/kg, i.p.) and memantine (5 mg/kg, i.p.) increased the basal ACh levels by 580%. In support of earlier findings with other NMDA receptor antagonists and AChE inhibitors, systemic administration of memantine and donepezil increased the basal ACh levels in the rat hippocampus. Concomitant administration of these drugs produced a greater increase in ACh levels than predicted from simple additivity indicating a synergistic effect of the two mechanisms involved, increased release by memantine and decreased breakdown by donepezil.