Ameliorative effect of tacrine on spatial memory deficit in chronic two-vessel occluded rats is reversible and mediated by muscarinic M1 receptor stimulation

Our previous study demonstrated that permanent two-vessel occlusion (2VO)-i nduced working memory deficit was improved by daily administration of tacri ne, a cholinesterase inhibitor. In this study, we investigated the mechanis m underlying the effects of tacrine in 2VO rats using the eight-arm radial maze task. Daily administration of tacrine (0.1 or 0.3 mg/kg i.p.) started 5 weeks after the 2VO operation significantly improved the maze performance . In the delay-interposition task, a significant impairment of maze perform ance was observed in the tacrine (0.3 mg/kg, i.p.)-treated rats at a delay of 90 min but not delays of 5 or 30 min. Sham-operated rats were not affect ed by delay. After leaving animals with no,further treatment for 4 weeks, t he tacrine-pretreated 2VO rats showed significantly impaired performance co mpared to the sham-operated control animals. However, the performance of th e tacrine-pretreated 2VO rats was significantly improved by restarting the daily administration of tacrine (0.3 mg/kg, i.p.). The effect of tacrine wa s reversed by the muscarinic antagonist scopolamine and the selective M1 an tagonist pirenzepine. Moreover, a microdialysis study revealed that tacrine (1 or 3 mg/kg, i.p.) increased the extracellular acetylcholine (ACh) level for a period of over 3 h in the cerebral cortex of 2VO rats. These finding s suggest that the ameliorative effect of tacrine on the spatial memory def icit in 2VO rats is reversible and may be mediated by stimulating the musca rinic M1 receptor via elevation of the extracellular ACh level in the brain . (C) 2000 Elsevier Science B.V. All rights reserved.