Pharmacological Manipulation of Memory Performance in Aged Monkeys
Jerry J. Buccafusco
Medical College of Georgia
Patients with Alzheimer's Disease have just begun to benefit from pharmacotherapy developed over the last several years. However, current approaches do not modify the course of the disease and they offer limited and transient benefit to a minority of patients. More recently, there has been a greater concentration of effort towards the development of disease-modifying therapies. Even with success in this area, it is very likely that there will continue to be an acute need for improving cognitive status in disease states and in normal aging. Over the past 12 years we have had the almost unique opportunity to study the effects of dozens of novel potential memory-enhancing agents in young mature and aged monkeys. From these studies (and from those of many others in the field) four statements may be made with reasonable certainty: 1) there exist a significant number of potential neural targets for cognitive/memory enhancement; 2) there appears to be a dose limit (usually very close to the maximal therapeutic effect) for each compound; 3) the upper limit of potential memory enhancement has not yet been reached, even in aged subjects; and 4) certain drugs that possess memory-enhancing actions also may exhibit neuroprotective or disease modifying potential. Exploiting multiple neural systems that have shown to be promising candidate therapeutic targets should widen the therapeutic window for treatment modalities and enhance the degree of maximal mnemonic improvement obtained to date. Studies in young and aged rhesus monkeys permit the determination of whether age modifies the response to these agents, which in turn may provide information regarding the selective vulnerability of each neural system to the aging process. Rhesus monkeys are well trained to perform food-motivated operant tasks designed to allow for the measurement of abilities which are relevant to human aging such as attention, strategy formation, reaction time, and memory for recent events. One of our goals has been to determine whether combinations of drugs that target different disease modifying mechanisms (like their cognitive actions) may provide an additive or synergistic protective effect when these compounds are combined. From these experiments the following long term goals have been developed: (1) To provide the framework for the development of novel compounds with multiple sites of actions, that allow for maximizing cognitive function and to provide disease modifying actions. (2) To exploit the knowledge gained regarding selective vulnerability of systems in aged subjects for diagnostic or future therapeutic approaches. (3) To study the neuroprotective actions of novel therapeutic approaches in vivo.
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