PHENSERINE, A NOVEL ACETYLCHOLINESTERASE INHIBITOR, ATTENUATES IMPAIRED LEARNING OF RATS IN A 14-UNIT T-MAZE INDUCED BY BLOCKADE OF THE N-METHYL-D-ASPARTATE RECEPTOR

THE present study evaluated the interaction of the glutamatergic and a cetylcholinergic systems in memory formation, with an overall emphasis on developing multi-system approaches for treating age-related cognit ive decline and Alzheimer's disease. Specifically, we used a 14-unit T -maze to investigate whether phenserine (PHEN), a long-acting acetylch olinesterase inhibitor, could overcome a learning deficit in rats indu ced by the NMDA receptor antagonist, 3-(+/-) 2-carboxypiperzin-4-yl) p ropyl phosphonic acid (CPP). Prior to drug treatment, 3-month-old male Fischer-344 rats were trained to criterion (13 of 15 shock avoidances ) in a straight runway. Twenty-four hours later, rats were given i.p. injections of saline (SAL), CPP (9 mg/kg) + SAL or CPP + PHEN (0.25, 0 .5 or 0.75 mg/kg) and received 15 massed training trials in a 14-unit T-maze. CPP significantly increased the number of errors made in the m aze relative to controls, and phenserine significantly reduced the num ber of errors made relative to rats receiving CPP only, with the lowes t dose being the most effective. These results provide further support of phenserine's potent, cognitive-enhancing properties, and suggest t hat combined modulation of glutamatergic and acetylcholinergic systems may be of potential benefit in developing new pharmacotherapies for A lzheimer's disease and age-related cognitive decline.