RODENT MODELS OF MEMORY DYSFUNCTION IN ALZHEIMERS-DISEASE AND NORMAL AGING - MOVING BEYOND THE CHOLINERGIC HYPOTHESIS

The Stone maze paradigm has been developed for use as a rat model of m emory impairment observed in normal aging and in Alzheimer's disease. Results from several studies have demonstrated the involvement of both cholinergic and glutamatergic systems in acquisition performance in t his complex maze task. Although results of clinical studies on the cog nitive enhancing abilities of cholinomimetics for treatment of memory impairment in Alzheimer's disease have been inconsistent, new classes of cholinesterase inhibitors offer greater potential for therapeutic e fficacy. The physostigimine derivative, phenserine, appears to have ma rked efficacy for improving learning performance of aged rats or of yo ung rats treated with scopolamine in the Stone maze. Declines in marke rs of glutamatergic neurotransmission in Alzheimer's disease and in no rmal aging suggest that pharmacological manipulation of this system mi ght also prove beneficial for cognitive enhancement. Treatment with gl ycine and/or polyamine agonists is suggested as a strategy for activat ing the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. In addition, the use of combined pharmacological activation of cholinergi c and glutamatergic systems is suggested. Manipulation of signal trans duction events should also be considered as a strategy for cognitive e nhancement. The influx of Ca2+ through the channel formed by the NMDA receptor stimulates the production of the oxyradical, nitric oxide (NO .), via the action of nitric oxide synthase (NOS). Compounds that inhi bit NOS activity impair acquisition in the Stone maze, suggesting an i nvolvement of NO.. Thus, strategies for inducing NO. production to enh ance cognitive performance may be beneficial. Because of the potential neurotoxicity for NO., this strategy is not straightforward. Although many new directions beyond the cholinergic hypothesis can be suggeste d, each has its potential benefits which must be weighed against its r isks. Nonetheless, an important unifying area for neurobiological rese arch examining mechanisms of normal brain aging and of age-related neu ropathology, as observed in Alzheimer's disease, might emerge from the identification of NO. as a simple molecule serving vital physiologica l functions but representing potential for neurotoxicity.