The study extended recent animal research to humans and tested predictions from influential computer models by neuroscientist Michael Hasselmo, DPhil, of Boston University's Center for Memory & Brain. The findings, published in February's Behavioral Neuroscience (Vol. 118, No. 1), suggest a central mechanism by which conditions that reduce acetylcholine, such as Alzheimer's disease, Parkinson's disease, dementia due to multiple strokes, multiple sclerosis and schizophrenia, cause problems with memory function, as well as the hallucinations and delusions that can occur in some of these conditions.

Moreover, it offers insight into the way that higher levels of acetylcholine modestly improve patients' attention, memory, daily living activities and behavioral symptoms. Cholinesterase inhibitors, which reduce cholinesterase--the enzyme that breaks down acetylcholine--are the only FDA-approved treatment for Alzheimer's. Understanding how they work to improve symptoms may help scientists develop more targeted and effective drugs, as well as avoid medications that weaken memory function.

In the study, researchers injected scopolamine into 12 healthy young adults. Used for decades to treat motion sickness and intestinal spasms, and as a sedative and pre-anesthetic before surgery, scopolamine blocks acetylcholine receptors in the brain and has long been known to impair certain types of learning and memory. Still, "This effect of anticholinergic drugs had not yet been linked to specific effects of acetylcholine within cortical structures," says Hasselmo.

Led by Alirezi Atri, MD, PhD, a neurologist at Massachusetts General Hospital and Harvard Medical School, the team measured how well participants learned new pairs of words, a common memory test. As expected, memory for word-pairs learned after scopolamine administration suffered significantly while memory for those pairs learned just before injection was spared. More to the point, scopolamine made it harder to learn when stimuli overlapped, creating "proactive" interference with learning--a condition more closely resembling everyday life.

"Proactive interference influences common tasks such as remembering where we parked the car or where we left the keys," says Hasselmo. "If one parks in the same lot every day, the memory of previous parking locations interferes when we try to encode and retrieve a new but similar parking place."

Two other groups of eight participants each served as controls that were tested on learning but were either given no drugs or given the synthetic anticholinergic glycopyrrolate to mimic the dry mouth that is produced when scopolamine is given. Glycopyrrolate, which crosses the blood-brain barrier more slowly and incompletely than scopolamine, was associated with subtle but measurable drops in learning.

The findings suggest, says Atri, that anticholinergic drugs may be useful as a kind of cognitive "stress test" for elderly patients who have an underlying dementia in its earliest stages, unmasking symptoms that would otherwise be hard to detect.

At the same time, he adds, "The chronic use of medications with anticholinergic [acetylcholine-reducing] effects by elderly people, especially those with cognitive impairment, would be expected to interfere with acquisition and future recall of new and, especially, related memories."

--R. ADELSON