Memory Drugs Could Backfire
Excerpt by Amanda Gardner, HealthDay

Regional differences in the brain may undercut the effectiveness of drugs that are being developed to enhance memory.

In fact, these drugs may actually impair working memory, which includes the ability to remember a phone number long enough to dial it.

The results of the study appear in the Nov. 5 online issue of Neuron.

Two parts of the brain are associated with different types of memory. The hippocampus has been associated with long-term memory formation, while the prefrontal cortex has been associated with working or functional memory (such as remembering the number of your babysitter). In a healthy individual, the two brain systems work together.

When a person ages, however, both hippocampal and prefrontal memory function can decline.

"Prefrontal cortex functions are essential to the information age and they naturally decrease with normal aging, so it's particularly important to see what this cortex needs and to give it back to this part of the brain," says study author Amy F.T. Arnsten, an associate professor and director of graduate studies in neurobiology at Yale University School of Medicine. "There's some deterioration in the hippocampus with normal aging, but what really erodes the hippocampus is Alzheimer's."

Experts believe that increasing the activity of an enzyme called protein kinase A (PKA) in the hippocampus may improve memory and other cognitive deficits. The drugs that are in development may do just that.

The problem, according to the authors of this new paper, is that a particular drug can have vastly different effects on different parts of the brain. In this study, they found that drugs that might benefit the hippocampus might also have unwanted, deleterious effects on the prefrontal cortex.

"Different regions of the brain which control different kinds of learning and memory may be affected differentially by drugs which are targeted at improving cognition," explains Paula Bickford, a professor of neurosurgery at the University of South Florida Center for Aging and Brain Repair in Tampa and past president of the American Aging Association. "They may improve one kind of cognition but impair a different type of cognition."

The researchers did a series of tests in rats and monkeys using drugs to increase or decrease PKA activity.

In the prefrontal cortex, inhibiting PKA improved functioning. PKA activation, on the other hand, impaired functioning. In other words, opposite processes seem to be in effect in the hippocampus and in the prefrontal cortex.

As people age, it appears that there is a decrease in PKA signaling in the hippocampus and a concomitant increase in the prefrontal cortex, meaning that different measures are needed to remediate the situation in each brain area. "A drug that would correct one would hinder the other," Arnsten says. "That's why this is so tough."

Right now, there are no memory enhancers that "work in people in any significant way," says William Thies, vice president of medical and scientific affairs at the Alzheimer's Association.

The current work doesn't necessarily put scientists further away from having memory-enhancing drugs. "It just makes it more clear the direction we need to go. It helps clarify what may or may not work," Bickford says.

"Unfortunately, this is the reality of our world. It's never quite as simple as we thought it was," Bickford adds. "Different brain regions have developed different chemical pathways, and that's how you get specificity within the brain. But it then makes it more difficult to design pharmaceuticals that are memory-enhancing."

"The prefrontal cortex is a huge part of the human cognitive experience, so it's particularly important when you're designing cognitive enhancers for humans that you take into account what this part of the brain needs," Arnsten says. "There are people who need to have their hippocampal function strengthened and for such people these drugs might be useful as long as doses would be kept low enough that they didn't interfere with the prefrontal cortex."

Bear in mind that these were also studies in animals, which doesn't guarantee the same principles will apply in humans.

More information

For more on memory and aging, visit UCLA or the University of Michigan.

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