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

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 [H-3]dizocilpine (MK-801) binding to synaptic membrane of rat cerebral cortex were compared. Their IC50 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 mu M, respectively. The rank order of potency is tacrine approximate to huperzine A > physostigmine > donepezil > huperzine B >> galanthamine. There is no correlation between their activities to inhibit [H-3]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. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.