The main focus of the proposed research is to develop and test an animal model to guide pharmacologic rehabilitation of cognitive dysfunction associated with Alzheimer's disease and senile dementia. The proposed research will: (a) determine the relative effectiveness of chronic oral single-drug versus combination-drug treatments in improving cognitive ability by studying the effect of dose on memory retention; (b) determine if improved retention test performance is due to drug effects on sensory acuity, learning, memory processing or on non-specific factors such as increased activity; (c) determine whether the single-drug and combination-drug treatments remain effective over 2, 4 and 6 month treatment periods; (d) determine if development of tolerance or hypersensitivity differs for single-drug and combination-drug treatments; and (e) determine if cumulative toxic effects develop with prolonged drug use. These questions will be studied in an animal model employing mice (18-30 months of age) treated chronically with oral cholinergic drugs (arecoline, tacrine, physostigmine). To determine if the effectiveness of the treatment observed at 2 months is maintained as the drug treatment continues, independent groups of mice will be trained and tested on a battery of tasks after 2, 4, or 6 months of drug treatment or no treatment (baseline control). In addition, behavioral tests of sensory threshold acuity and behavioral toxicity will be conducted to determine if transient or cumulative toxic effects are associated with the drug treatments and if single-drug and combination-drug treatments differ in their tendency to induce "side effects".