Normal aging and Alzheimer's disease are characterized by severe deficits in the ability to learn new information while inhibiting the use of previously relevant information. There is accumulating evidence that the neurotransmitter, serotonin (5-HT) may enable learning when conditions require a shift in strategies. More recent findings suggest that activation of 5-HT4 receptors, in particular, may improve cognition, as well as produce neuroprotection. The long-term objective of this proposal is to determine whether treatment with a selective, 5-HT4 agonist improves learning when conditions demand a shift in response patterns in young adult and aged rats. Previous attempts to alleviate cognitive deficits in aging and Alzheimer's disease have focused on directly altering the brain cholinergic system. This approach has had limited success. There is recent evidence that 5-HT4 agonist treatment may improve memory, however, unknown is whether activation of 5-HT4 receptors enhances learning when conditions require a shift in strategies. One study will examine whether administration of the selective 5-HT4 agonist, RS 67333, in young adult and aged rats affects reversal learning in a two-choice place discrimination. Aged individuals and those with Alzheimer's disease sometimes only manifest cognitive deficits under conditions that have an increased level of difficulty. A second experiment will determine whether administration of RS 67333 in young adult and aged rats affects reversal learning in a four-choice place discrimination. Because two of the choices in this task act as distracter choices this study will be able to determine whether increases in interference may contribute to possible age-related impairments and whether activation of 5-HT4 receptors may reduce this deficit. Activation of brain 5-HT4 receptors is known to affect acetylcholine release. A third experiment will determine whether RS 67333 concomitantly enhances striatal acetylcholine output and reversal learning. These initial experiments will be essential in developing a broader research program to understand what neurochemical mechanisms in specific brain circuitry is altered that leads to cognitive flexiblity deficits in aging. Overall, the findings from the proposed studies will provide new and significant information on the processes underlying possible age-related deficits in cognitive flexibility and whether activation of 5-HT4 receptors may be effective in alleviating cognitive flexibility impairments. Normal aging and Alzheimer's disease is characterized by deficits in learning and the ability to switch strategies. The major goal of this project is to determine whether activating serotonin 4 receptors may alleviate learning deficits in aging. These studies have the potential of developing a novel treatment for the learning and memory deficits observed in aging and Alzheimer's disease. [unreadable] [unreadable] [unreadable]