Comparison of the effects of cholinesterase inhibitors on [ 3H]MK-801 binding in rat cerebral cortex

Abstract

Huperzine A, a selective inhibitor of acetylcholinesterase, was recently demonstrated to exert an antagonist effect on N-methyl- d-aspartate (NMDA) receptor in rat cerebral cortex. In the present study, the effects of six cholinesterase inhibitors, e.g. huperzine A, huperzine B, tacrine, donepezil (E2020), physostigmine and galanthamine on [ 3H]dizocilpine (MK-801) binding to synaptic membrane of rat cerebral cortex were compared. Their IC 50 values (mean ± SD) were 36.9±12.1, 316.8±93.2, 33.2±3.7, 135.0±15.1, 50.4±7.4, and 3344±295 μM, respectively. The rank order of potency is tacrine ≈ huperzine A>physostigmine>donepezil>huperzine B≫galanthamine. There is no correlation between their activities to inhibit [ 3H]MK-801 binding and to inhibit acetylcholinesterase ( r=+0.563, P=0.245). The results suggest that most cholinesterase inhibitors available exhibit an antagonist effect on NMDA receptor in rat cerebral cortex in addition to their inhibitory effect on acetylcholinesterase.