Nicotine-Like Drugs Can Enhance Learning, Memory In Rat Model Of Alzheimer's Disease

Duke behavioral pharmacologist Edward Levin said in a report prepared for presentation Sunday (Nov. 8) at the Society of Neuroscience annual meeting that nicotine-like compounds can actually help restore the ability to learn and remember in rats that have brain lesions similar to those found in Alzheimer's disease patients.

The research showed that rats given a drug called AR-R 17779, a proprietary compound, performed significantly better than untreated rats on standard radial arm maze learning and memory tests.

The compound was developed by Astra Arcus USA, a pharmaceutical company based in Worcester, Mass., which also supported the research study. AR-R 17779 is one of a new class of drugs aimed at combating the learning and memory deficits associated with Alzheimer's disease. These compounds work by docking to specific sites on the surface of brain cells called acetylcholine receptors. Nicotine or a nicotine look-alike can activate these receptors, which enhance the brain's ability to learn and remember. Some studies suggest that nicotinic receptor stimulation, especially activation of a specific nicotinic receptor sub-type known as alpha7 that AR-R 17779 binds to, may be able to protect brain cells from deterioration caused by Alzheimer's disease.

Nicotine itself simultaneously activates many types of receptors and inactivates others. The effects on some receptors increase attention and decrease anxiety, appetite and pain, while others elevate blood pressure and heart rate.

"We are excited about this class of compounds because they act very selectively on one sub-type of receptors, as opposed to nicotine, which acts on many, many systems throughout the body," Levin said. "The hope is that these drugs will have beneficial effects on cognition without some of the cardiovascular side effects associated with nicotine."

Levin and his colleagues tested the ability of AR-R 17779 to boost learning and memory in rats placed on a standard radial arm maze test, a wagon-wheel shaped structure consisting of a platform with planks radiating from it. At the end of each plank is a food reward. Once eaten, the food is not replaced. Normal rats quickly learn that it is not worth their effort to go down the same plank twice, whereas rats that have lesions in their brains that mimic Alzheimer's disease show significantly slower learning and memory of the task.

"When we injected the impaired rats with the compound 20 minutes before testing, the animals showed significantly improved learning and even a reversal of the working memory impairment normally seen in these animals," Levin said. "However, further testing will certainly be required to confirm and expand on these results."

Levin also is conducting clinical trials using nicotine skin patches to try to improve attention and memory in Alzheimer's disease patients.

"Memory loss is one of many symptoms that patients with Alzheimer's and other dementias develop as their brain cells deteriorate," Levin said. "As patients' memory and comprehension deteriorate, performing ordinary tasks becomes more difficult. We know that nicotine or nicotine-like drugs may not be a cure-all for Alzheimer's disease, but if we could prolong the period of time that patients can be independent and functional, it could mean a much better quality of life for them and their care givers."

The results of Levin's human studies are expected in 1999. "We would certainly discourage the use of nicotine products or taking up smoking for Alzheimer's disease patients," Levin said. "Our goal is to find a nicotine-like substance that will give the beneficial effects of nicotine without the harmful side effects or addictive ability."