Washington, D.C.-A short-term drug regimen offers long-lasting reversal of a certain form of memory loss in monkeys given antipsychotic medications, researchers report March 17 in the journal,Science.
Known as "working" memory, this function is critical because it allows individuals to briefly hold information in mind during thinking and comprehension tasks. Working memory can become disturbed in people with many conditions, including schizophrenia.
New research may ultimately suggest improved treatment strategies for people suffering from schizophrenia, Parkinson's disease or age-related memory loss, according to Science author Patricia S. Goldman-Rakic, a professor of neuroscience, neurology and psychiatry at the Yale University School of Medicine.
Commonly prescribed for schizophrenia, antipsychotic drugs such as haloperidol block dopamine D2 receptors within the brain, says Stacey A. Castner, an associate research scientist and lead author of the paper. In response to this pharmaceutical "blockade," Castner says, the D2 receptors proliferate and increase their ranks.
Unfortunately, while so many D2 receptors are seeking dopamine stimulation, D1 receptors located in a brain region tied to working memory tend to dwindle in number. This discovery inspired the Yale study because a decline in D1 receptor function may result in memory impairments for people who take haloperidol-type medications, says Goldman-Rakic. The team, including coauthor Graham V. Williams, an associate research scientist, sought to reverse this decline by stimulating D1 receptor function.
According to the Science paper, intermittent treatment with an experimental but not yet available drug, ABT 431, effectively reversed haloperidol-induced memory loss in six female monkeys, and the improvement has been sustained for more than a year.
"What's remarkable about this particular drug is that patients would only need to use it for a short period of time to achieve long-lasting effects," says Goldman-Rakic, director of the Yale laboratory where the research was conducted. "By stimulating D1 receptors, the medication might also prove useful to people with other conditions characterized by low dopamine levels, such as Parkinson's disease, or memory loss related to aging. In these diseases, long-term treatment often becomes part of the problem because of unwanted side effects."
In the future, she says, it might be possible to help patients with schizophrenia and others, by offering periodic injections or oral administration of the study drug or a similar compound.
In the Science study, a half-dozen monkeys were trained to complete a series of memory-intensive tasks. Within six months to a year, each animal had achieved a consistent level of performance, correctly completing 75 percent of all attempts. Yet, after receiving haloperidol at levels comparable to the typical human dose, five monkeys demonstrated "significant memory impairment," making errors associated with their ability to remember information, even for a short period of time.
Treatment with ABT 431 helped the monkeys regain their performance. Each animal received the drug for blocks of five consecutive days, followed by a "washout period" of two weeks or more. After therapy, "the monkeys showed increasingly extended periods of sustained improvement on the working memory tasks, which carried over into the washout periods between coadministrations, despite continued haloperidol treatment," the Science paper concludes. Castner says this reversal has been maintained for up to two years in some cases.
"What's needed now are clinical trials," Goldman-Rakic says. "This could help so many people."
Research described in this news release received support from Hoechst Marion Rousell (now Aventis Pharmaceuticals); the National Institute of Mental Health; and the National Institute of Drug Abuse.
ORDER ARTICLE #27: "Reversal of Antipsychotic-Induced Working Memory Deficits by Short-Term Dopamine D1 Receptor Stimulation," by S. A. Castner, G. V. Williams, and P. S. Goldman-Rakic at Yale U. School of Medicine in New Haven, CT. CONTACT: Patricia S. Goldman-Rakic at 203-785-4808 (phone), 203-785-5263 (fax), or patricia.goldman-rakic@yale.edu (email) or Stacy Castner at 203-737-4371/ 203-785-6211 (phone), or castner@biomedi.med.yale.edu (e-mail) For copies of this article, please email scipak@aaas.org, call 202-326-6440, or fax this form to 202-789-0455.
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Science