Memory drugs abuse brain in long term



In a new study published in Neuron magazine, Yale researchers have found that memory-enhancing drugs may actually harm working memory.

Memory function is controlled by many portions of the brain. Memory-enhancing drugs primarily target the hippocampus, the known site of long-term memory consolidation. Another portion of the brain, the prefrontal cortex, is important in human cognitive acts such as intelligent thought, planning and organization. Memory-enhancing drugs work by activating an enzyme called protein kinase A. Higher levels of protein kinase A increase function in the hippocampus, but impair function in the prefrontal cortex.

“The newsworthy part of this in a general way is that bio-tech companies have been focusing on this intracellular chemical pathway as a way of developing memory enhancers,” said Dr. Amy Arnsten, associate professor and director of graduate studies of neurobiology at the Yale School of Medicine. “We’ve been studying the chemical needs of the prefrontal cortex, and found they’re very different from those of the hippocampus, and often, opposite.”

Yale is one of the premier research centers studying the prefrontal cortex, which functions very differently from the hippocampus, Arnsten said. She said she hopes the findings will encourage scientists and drug developers to treat the brain as a heterogeneous organ.

Researchers also included graduate student Brian Ramos GRD ’05 and School of Medicine professor Ronald Duman. Duman and Ramos studied memory loss in aging rats by measuring varying levels of protein kinase A.

“[Duman] and [Ramos] showed that an aged rat with poor memory consolidation had overacting protein kinase A,” Arnsten said. “Animals in the worst shape had the most kinase A.”

Arnsten said the prefrontal cortex provides evidence of highly advanced evolution in human beings. Biotechnology companies have focused on brain function in less evolved creatures like sea slugs and fruit flies, experiments which may not provide accurate representations of human physiology.

“[One company] based their research on memory function and consolidation of long term memory in the fruit fly,” Arnsten said. “[In flies] memory does get stored in the hippocampus, but these are ancient functions. The prefrontal cortex, which is much more highly evolved, has different needs.”

Arnsten said brain function between the two areas differentiates further with advancing age, and the hippocampus and prefrontal cortex are associated with different aspects of memory loss. Their differing functions may be important in deciding which areas should be targeted in drug development.

“The differences [between the hippocampus and the prefrontal cortex] become more exaggerated with advancing age,” Arnsten said. “Normal aging is associated with deficits in prefrontal cortex, and Alzheimer’s is in the hippocampus.”

The study was funded by the National Institute for the Aging (NIA), part of the National Institute of Health. Dr. Molly Wagster, program director for neuropsychology of aging research at the NIA, said while the findings are not yet directly translatable into clinical practice, the information will change the ways scientists consider the brain when developing drugs.

“It’s a bit premature to say that we’re going to start changing all of our treatment regiments based on this,” Wagster said. “We need to consider very closely the complexity of the human brain when designing drugs that are impacting something such as memory. Memory is not a [one]-dimensional — function.”

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