Enzyme regulates brain pathology induced by cocaine, stress

November 8, 2007

Researchers have uncovered a key genetic switch that chronic cocaine or stress influences to cause the brain to descend into a pathological state. In studies with mice they showed how chronic cocaine changes gene activity to enhance the addictive reward from the drug. And they showed similarly how chronic stress induces the same kinds of changes that hypersensitizes the brain, causing depression-like symptoms.

The researchers said their basic finding in the animals could lead to better treatments for addiction, depression and other psychiatric disorders.

Eric Nestler and colleagues published their findings in the November 8, 2007, issue of the journal Neuron, published by Cell Press.

In their experiments, the researchers explored how chronic cocaine or stress exerts “epigenetic” control of genes in the brain. Such control involves repressing or activating genes by altering the structure of the chromatin that enwraps genes. Specifically, the researchers explored whether chronic cocaine or stress affect an enzyme called histone deacetylase 5 (HDAC5). Normally, HDAC5 represses specific genes by removing molecules called acetyl groups from the histone proteins that make up the chromatin surrounding them. The researchers’ previous studies had shown that chronic cocaine administration in mice caused an increase in acetyl groups in a brain region called the nucleus accumbens (NAc), known to be involved in response to cocaine or stress.

The researchers’ studies showed that giving mice chronic cocaine led to a reduction in HDAC5, allowing some 172 genes to be activated. What’s more, they found that this loss of HDAC5 in the NAc made the mice more sensitive to the reward of chronic cocaine. They determined the animals’ reward-sensitivity to cocaine by measuring the mice’s preference for an area of a box that they were taught to associate with receiving cocaine.

The researchers also studied whether the animals’ adaptation to chronic stress involved HDAC5 levels. In these experiments, they exposed mice to aggressive mice and measured the resulting depressive behavior. The researchers found that such stress also reduced HDAC5 function, although through a different mechanism than for chronic cocaine.

“These data demonstrate a crucial role for HDAC5 in regulating behavioral adaptations to chronic stress as well as chronic cocaine and suggest that HDAC5 contributes to a molecular switch between acute stress responses and more long-lasting depression-like maladaptations,” wrote the researchers.

“The functions of HDAC5 described here provide new insight into the pathogenesis of drug addiction, depression, and other stress-related syndromes,” they wrote. “This fundamentally new insight into the molecular underpinnings of chronic maladaptation in brain could lead to the development of improved treatments for addiction, depression, and other chronic psychiatric disorders.”

Source: Cell Press

Explore further: Depression treatment needs overhaul

Related Stories

Depression treatment needs overhaul

November 3, 2017
The way depression is diagnosed and treated needs a major overhaul, say authors of a new review article in the scientific journal Brain, Behavior, and Immunity.

Is meth use destroying vets' hearts?

November 14, 2017
(HealthDay)—Methamphetamine appears to be damaging the hearts of U.S. military veterans at an increasing rate, researchers report.

New study suggests chronic cocaine use causes profound metabolic changes, reducing the body's ability to store fat

August 9, 2013
Chronic cocaine use may reduce the body's ability to store fat, new research from the University of Cambridge suggests.

Cocaine users' brains unable to extinguish drug associations

September 11, 2017
Cocaine-addicted individuals say they find the drug much less enjoyable after years of use, but they have great difficulty quitting. A new brain imaging study led by researchers at the Icahn School of Medicine at Mount Sinai ...

Mechanism that reduces effect of cocaine on brain discovered

May 19, 2016
A type of brain cell known as microglia plays a key role in reducing the effects of cocaine in the brain, according to a major study by a team from the Research Institute of the McGill University Health Centre (RI-MUHC) in ...

Recreational cocaine use linked to conditions that cause heart attack

November 5, 2012
People who regularly use cocaine socially have stiffer arteries, higher blood pressure and thicker heart wall muscle than non-users, according to research presented at the American Heart Association's Scientific Sessions ...

Recommended for you

Researchers illustrate how muscle growth inhibitor is activated, could aid in treating ALS

January 19, 2018
Researchers at the University of Cincinnati (UC) College of Medicine are part of an international team that has identified how the inactive or latent form of GDF8, a signaling protein also known as myostatin responsible for ...

Bioengineered soft microfibers improve T-cell production

January 18, 2018
T cells play a key role in the body's immune response against pathogens. As a new class of therapeutic approaches, T cells are being harnessed to fight cancer, promising more precise, longer-lasting mitigation than traditional, ...

Weight flux alters molecular profile, study finds

January 17, 2018
The human body undergoes dramatic changes during even short periods of weight gain and loss, according to a study led by researchers at the Stanford University School of Medicine.

Secrets of longevity protein revealed in new study

January 17, 2018
Named after the Greek goddess who spun the thread of life, Klotho proteins play an important role in the regulation of longevity and metabolism. In a recent Yale-led study, researchers revealed the three-dimensional structure ...

The HLF gene protects blood stem cells by maintaining them in a resting state

January 17, 2018
The HLF gene is necessary for maintaining blood stem cells in a resting state, which is crucial for ensuring normal blood production. This has been shown by a new research study from Lund University in Sweden published in ...

Magnetically applied MicroRNAs could one day help relieve constipation

January 17, 2018
Constipation is an underestimated and debilitating medical issue related to the opioid epidemic. As a growing concern, researchers look to new tools to help patients with this side effect of opioid use and aging.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.