The research, published online in Neuron on November 5, analyzes the effects of these drugs on multiple brain regions and suggests that the medications may actually have hazardous consequences on higher-order thought processes that are regulated by the prefrontal cortex.
The hippocampus has been associated with long-term memory formation, while the prefrontal cortex has been associated with working memory. In a healthy brain, the two brain systems work together to optimize cognitive abilities. Compounds that increase the activity of an enzyme called protein kinase A (PKA) improve long-term hippocampal-dependent memory in aged mice and have been proposed as possible therapeutics for memory deficits in elderly humans. Because aging impairs both hippocampal-dependent and prefrontal memory function, Dr. Amy F.T. Arnsten, Dr. Ronald S. Duman, and colleagues from Yale University investigated how agents that increase PKA activity influence prefrontal cortical function in animals. The researchers observed that, in contrast to hippocampal-dependent long-term memory, dynamic working memory in older animals is impaired by PKA stimulation and enhanced by PKA inhibition. Moreover, they found that PKA is disinhibited in the prefrontal cortex of aged rats with naturally occurring working memory deficits.
The researchers conclude that aging has diverse effects on different brain regions-specifically, decreasing PKA activity in the hippocampus and increasing it in the prefrontal cortex. These observations suggest that compounds designed to increase PKA activity may exacerbate age-dependent decline in working memory.
According to Dr. Arnsten, "We need to respect the diverse chemical needs of higher cortical brain regions if we are to develop effective cognitive enhancers for the elderly."