Mice Study Identifies Role of Stress in DepressionA new study on mice is helping researchers learn how stress affects mood. Scientists believe the findings could stimulate the creation of new medications to address a variety of mental and addictive disorders.

Researchers say that blocking the stress cascade in brain cells can help reduce the effects of stress, which can include anxiety, depression and the pursuit of addictive drugs.

In the study, scientists discovered that when mice are exposed to stress, a protein called p38α mitogen-activated protein kinase (MAPK) influences the animal’s behavior, contributing to depression-like symptoms and risk for addiction.

This protein is activated by receptors on neurons to regulate serotonin, a key neurotransmitter that helps regulate mood.

Details on the research study are published in the journal Neuron.

Experts believe exposure to stress causes the brain to releases hormones that specifically interact with receptors on neurons. Those receptors, in turn, activate p38α MAPK, which then interacts with the serotonin transporter in the cells to reduce the amount of available serotonin.

In this study, scientists looked at a brain region, called the dorsal raphe nucleus, where many stress-related factors and serotonin combine.

They found that after stress exposure, mouse brains activate p38α MAPK, lowering serotonin levels and triggering depression-like behaviors as well as drug-seeking behavior in the mice.

Stressed animals withdrew and did not interact with other mice. In animals that had been given cocaine injections while in specific places in their cages, stress made them more likely to physically seek out those locations where they had received the drug.

“We call these responses ‘depression-like’ and ‘addiction-like’ behaviors because we can’t ask mice if they’re addicted or sad,” said lead researcher Michael R. Bruchas, Ph.D. “But just as depressed people often withdraw from social interactions, stressed mice do the same thing. We also observed that stressed mice return more often to the place where they received cocaine.”

Researchers then used a relatively new genetic technology to disable the p38α MAPK protein only in cells of the brain’s serotonin system. Without the p38α protein, the stress-exposed mice no longer withdrew from social interactions, displayed depression-like behavior or sought drugs.

Bruchas and his colleagues also studied mice exposed to what they call social defeat stress.

“We put a mouse into an enclosure with an ‘aggressor’ mouse,” Bruchas says.

“Some mice, like some humans, are more dominant and aggressive. When a non-aggressive mouse is put into a cage with an aggressive animal, that aggression causes stress similar to what we might see in an adult human working for a difficult boss or a teenager who has to deal with a bully at school.”

Just as interacting with a “bully” mouse is similar to dealing with stressful environments, the cascade of events in the brain that contributes to serotonin reduction appears to be similar in both mice and humans.

“When people take antidepressant drugs called selective serotonin reuptake inhibitors, or SSRIs, to relieve depression, the drugs act on a cellular pump called the serotonin transporter, and this results in more serotonin in the brain,” Bruchas says.

“We think that the involvement of the p38α protein and kappa-opioid receptors represents an important finding in figuring out how it is that cells regulate depressive and addictive behaviors.”

In his new laboratory at Washington University, Bruchas says he plans to test whether the same p38α MAPK protein is involved when the drug is nicotine or amphetamine.

“It will be important to determine whether this pathway is conserved for drugs of abuse other than cocaine,” he says. “If so it will further highlight the importance of working with chemists to target this pathway for potential therapies.”

Bruchas also plans to look at other brain areas to learn whether similar responses are occurring in response to stress.

Source: Washington University School of Medicine