New pharmacological strategies for cognitive enhancement using a rat model of age-related memory impairment.

We have developed the Stone maze paradigm for use as a rat model of memory impairment observed in normal aging and in Alzheimer's disease. Evidence produced thus far clearly implicates both the cholinergic and glutamatergic systems in acquisition performance in this complex maze task. Although results have been very inconsistent regarding the cognitive enhancing abilities of cholinomimetics for use in Alzheimer's disease, new classes of cholinesterase inhibitors may offer greater therapeutic efficacy. The use of glycine and polyamine agonists appears to be a viable strategy for positive modulation of the NMDA receptor. In addition, an approach that combines stimulation both of cholinergic and glutamatergic systems may have greater potential than agonism of either separately. Manipulation of signal transduction events might also have potential for cognitive enhancement. The influx of Ca2+ through the NMDA receptor stimulates production of NO via the action of NOS. By using NARG to block NOS activity, we have demonstrated in rats that NO production appears to influence learning in the Stone maze. We are currently exploring the age-related changes in NOS activity in specific brain regions of rats to determine if loss in the NO generating system is related to age-related memory impairment observed in the Stone maze. In addition, we are exploring pharmacological strategies for inducing NO production; however, because of the potential neurotoxicity for NO overstimulation, this strategy will present some obstacles. The identification of NO as a simple molecule serving vital physiological functions but representing potential for neurotoxicity presents an important unifying area for neurobiological investigations searching for mechanisms of normal brain aging and of age-related neuropathology, as observed in Alzheimer's disease.