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Stress impairs thinking via mania-linked enzyme

An errant enzyme linked to bipolar disorder, in the brain's prefrontal cortex, impairs cognition under stress, an animal study shows. The disturbed thinking, impaired judgment, impulsivity, and distractibility seen in mania, a destructive phase of bipolar disorder, may be traceable to overactivity of protein kinase C (PKC), suggests the study, funded by the National Institutes of Health's (NIH) National Institute of Mental Health (NIMH) and National Institute on Aging (NIA), and the Stanley Foundation. It explains how even mild stress can worsen cognitive symptoms, as occurs in bipolar disoder, which affects two million Americans.

Abnormalities in the cascade of events that trigger PKC have also been implicated in schizophrenia. Amy Arnsten, Ph.D. and Shari Birnbaum, Ph.D. of Yale University, and Husseini Manji, M.D., of NIMH, and colleagues, report on their discovery in the October 29, 2004 issue of Science.

"Either direct or indirect activation of PKC dramatically impaired the cognitive functions of the prefrontal cortex, a higher brain region that allows us to appropriately guide our behavior, thoughts and emotions," explained Arnsten. "PKC activation led to a reduction in memory-related cell firing, the code cells use to hold information in mind from moment-to-moment. Exposure to mild stress activated PKC and resulted in prefrontal dysfunction, while inhibiting PKC protected cognitive function."

"In the future, drugs that inhibit PKC could become the preferred emergency room treatments for mania," added Manji, currently Director of NIMH's Mood and Anxiety Disorders Program, who heads a search for a fast-acting anti-manic agent. "All current treatments lithium, valproate, carbamazepine and antipsychotics take days, if not weeks, to work. That's because they're likely acting far upstream of where a key problem is, namely in the PKC pathway. Since PKC inhibitors could act more directly, they might quench symptoms more quickly. Patient
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Contact: Jules Asher
NIMHpress@nih.gov
301-443-4536
NIH/National Institute of Mental Health
29-Oct-2004


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