Featured Research

from universities, journals, and other organizations

Stress Impairs Thinking Via Mania-Linked Enzyme

Date:
November 3, 2004
Source:
NIH/National Institute Of Mental Health
Summary:
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.

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 2 million Americans.

Related Articles


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. Patients could carry PKC inhibitors and take them preventively, as soon as they sense a manic episode coming on.”

Clinical trials of a PKC inhibitor, the anti-cancer drug tamoxifen, are currently underway in bipolar disorder patients. However, these may be more important for proof-of-concept than therapeutic utility, according to Manji, who says side effects will likely rule out tamoxifen itself as a practical treatment for mania. “While there are likely other pathways involved, PKC appears to be very important for bipolar disorder,” he noted.

The fact that the current anti-manic drugs ultimately reduce PKC activity suggests that PKC may be a final common target of these treatments and may play a key role in bipolar disorder. Studies have also found signs of increased PKC activity in bipolar patients’ blood platelets and in the brain cells of deceased patients. Susceptibility to bipolar disorder may involve variants of genes that code for a key PKC precursor and for a stress-sensitive signaling protein that normally puts the brakes on PKC activity.

The new study shows how PKC triggers cognitive symptoms in response to stress. When the stress-sensitive messenger chemical norepinephrine binds to receptors on cell membranes in the prefrontal cortex, it activates PKC through a cascade of events. The enzyme then travels out to the cell membrane, opening ion channels that heighten the cell’s excitability, and stoking protein machinery that propels neurotransmitters into the synapse. PKC also moves into the cell’s nucleus, where it turns on genes.

To tease out PKCs role, the researchers selectively targeted the prefrontal cortex in rats and monkeys performing working memory tasks with PKC activators, inhibitors, norepinephrine-like and stress-inducing drugs — alone and in combination. They also found that by blocking PKC, the anti-manic drugs lithium and carbamazepine protected monkeys’ prefrontal cortex functioning from impairment by a norepinephrnine-like drug. The researchers traced impairment to a reduction in memory-related firing of single cells in the prefrontal cortex, which was reversible by a PKC inhibitor.

Genetic and biochemical studies indicate that PKC may also be overactive in the brains of patients with schizophrenia. Antipsychotics, which are used to treat bipolar disorder as well as schizophrenia, block receptors in the brain that activate PKC.

Also participating in the study were: Dr. Peixiong Yuan, NIMH; Dr. Min Wang, Susheel Vijayraghavan, Allyson Bloom, Douglas Davis, Kevin Gobeske, Yale University; Dr. David Sweatt, Baylor College of Medicine.

To learn more, visit the following links:

Bipolar Disorderhttp://www.nimh.nih.gov/healthinformation/bipolarmenu.cfm

Schizophreniahttp://www.nimh.nih.gov/healthinformation/schizophreniamenu.cfm


Story Source:

The above story is based on materials provided by NIH/National Institute Of Mental Health. Note: Materials may be edited for content and length.


Cite This Page:

NIH/National Institute Of Mental Health. "Stress Impairs Thinking Via Mania-Linked Enzyme." ScienceDaily. ScienceDaily, 3 November 2004. <www.sciencedaily.com/releases/2004/11/041103030409.htm>.
NIH/National Institute Of Mental Health. (2004, November 3). Stress Impairs Thinking Via Mania-Linked Enzyme. ScienceDaily. Retrieved November 27, 2014 from www.sciencedaily.com/releases/2004/11/041103030409.htm
NIH/National Institute Of Mental Health. "Stress Impairs Thinking Via Mania-Linked Enzyme." ScienceDaily. www.sciencedaily.com/releases/2004/11/041103030409.htm (accessed November 27, 2014).

Share This


More From ScienceDaily



More Mind & Brain News

Thursday, November 27, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Are Female Bosses More Likely To Be Depressed?

Are Female Bosses More Likely To Be Depressed?

Newsy (Nov. 24, 2014) — A new study links greater authority with increased depressive symptoms among women in the workplace. Video provided by Newsy
Powered by NewsLook.com
Winter Can Cause Depression — Here's How To Combat It

Winter Can Cause Depression — Here's How To Combat It

Newsy (Nov. 23, 2014) — Millions of American suffer from seasonal depression every year. It can lead to adverse health effects, but there are ways to ease symptoms. Video provided by Newsy
Powered by NewsLook.com
Could Your Genes Be The Reason You're Single?

Could Your Genes Be The Reason You're Single?

Newsy (Nov. 21, 2014) — Researchers in Beijing discovered a gene called 5-HTA1, and carriers are reportedly 20 percent more likely to be single. Video provided by Newsy
Powered by NewsLook.com
Milestone Birthdays Can Bring Existential Crisis, Study Says

Milestone Birthdays Can Bring Existential Crisis, Study Says

Newsy (Nov. 21, 2014) — Researchers find that as people approach new decades in their lives they make bigger life decisions. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:

Strange & Offbeat Stories

 

Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins