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Researchers have discovered how stress can influence drug-seeking and depressive behavior, leading to a possible new approach of addiction treatment involving the blocking of stress activity in the brain.

When untreated or mishandled, accumulative stress can encourage adverse mental health and human behaviors including depression, anxiety, poor productivity, and substance use. Lead author of the study Dr. Michael Bruchas of Washington University in St. Louis’ Department of Medicine and his research team investigated the dorsal raphe nucleus brain region in mice to help identify the mechanisms that underlie stress responses in the brain, which until now have remained scarcely understood in the medical field. In their study, the researchers exposed wild-like mice to stress-induced situations. When exposed to stress, according to the researchers, the brain undergoes a chain of events that affect one’s ability to regulate mood. First, stress causes the brain to release hormones which then interact with the kappa-opioid receptors in neurons. These neuron receptors activate a protein called p38α mitogen-activated protein kinase (MAPK). Then, the p38α MAPK protein interacts with the serotonin transporters in the brain cells, depleting the amount of serotonin available. Serotonin is an important neurotransmitter that helps regulate mood; without a sufficient amount of serotonin, stress-related behaviors (such as depression and addiction) are more likely to occur.

The researchers state that the stressed-induced events that occur in the mice’s brains are very similar to that which occurs in human brains when undergoing stress. To parallel a common stressful environment that humans endure—as in dealing with a bully or dominating boss—the researchers exposed the mice to social defeat stress, in which a non-aggressive mouse is enclosed inside a cage with an aggressor mouse. In this situation, the stressed mice exhibit the same cascade of brain events as stressed humans which lead to the reduction of available serotonin.

During their mice study, the researchers identified that mice undergoing stress were more likely to socially withdraw from the other mice, indicative of depressive-like behavior. Additionally, the researchers administered cocaine injections to some of the mice while in specific locations in their cages. When stressed, these mice were likelier to return to these locations, demonstrating a stressed-induced, drug-seeking behavior.

Then, using what is known as a conditional gene knockout approach, the researchers blocked the p38α MAPK protein in some of the mice’s brains, which is involved in their mood and behavior and responsible for reducing serotonin needed to manage stress. With the p38α MAPK protein disabled, mice exposed to stress no longer exhibited depressive-like or addictive-like behaviors, such as social withdrawal or drug seeking.

Modern pharmacological treatment of depression may involve the administration of selective serotonin reuptake inhibitors, or SSRIs, which relieve depression by boosting the serotonin transporters in cells and encouraging the presence of serotonin. Based on their studies’ findings, the research team believes that the p38α MAPK protein’s interaction with the kappa-opioid neuron receptors in the brain is significant to the cellular processes of depression or addictive behaviors. Investigating these interactions could help researchers better understand how to treat these mood and behavior symptoms. For future research, Bruchas and his colleagues are seeking to discover whether blocking the p38α MAPK protein is also effective in treating addiction to other substances, including nicotine and amphetamine. Also, the research team will be studying whether the p38α MAPK protein affects long-term addiction and risk for relapse. Identifying the p38α MAPK protein’s involvement in these addictive behaviors could help establish new, more resilient therapeutic treatments.

The researchers’ new study is currently available online in the scientific journal Neuron.

REFERENCES/RESOURCES:

http://news.wustl.edu/news/Pages/22553.aspx

Bruchas, Michael R., Abigail G. Schindler, Haripriya Shankar, Daniel I. Messinger, Mayumi Miyatake, Benjamin B. Land, Julia C. Lemos, Catherine E. Hagan, John F. Neumaier, Albert Quintana, Richard D. Palmiter, and Charles Chavkin. 11 August 2011. Neuron 71 (3):498–511. DOI: 10.1016/j.neuron.2011.06.011. Available online: http://www.cell.com/neuron/abstract/S0896-6273(11)00515-0