Researchers at the University of Southern California have found that pathological rage can be blocked in mice, suggesting potential new treatments for severe aggression.
In a new study, researcher identified a brain receptor that malfunctions in overly hostile mice, resulting in aggression, which is characterized by sudden violence, explosive outbursts and hostile overreactions to stress. When researchers shut down the brain receptor, which also exists in humans, the excessive aggression disappeared.
The findings could be helpful in developing drugs for pathological aggression, which can be a component of Alzheimer’s disease, autism, bipolar disorder and schizophrenia, among other common psychological disorders, according to Marco Bortolato, M.D., Ph.D., lead author of the study and research assistant professor of pharmacology and pharmaceutical sciences at the USC School of Pharmacy.
“From a clinical and social point of view, reactive aggression is absolutely a major problem,” he said. “We want to find the tools that might reduce impulsive violence.”
A large body of independent research, including past work by Bortolato and senior author Jean Shih, Ph.D., a professor in pharmacology and pharmaceutical sciences at USC, identified a specific genetic predisposition to pathological aggression: Low levels of the enzyme monoamine oxidase A (MAO A). Both male humans and mice with congenital deficiency of the enzyme respond violently in response to stress, according to the researchers.
“The same type of mutation that we study in mice is associated with criminal, very violent behavior in humans,” Bortolato said. “But we really didn’t understand why that it is.”
Bortolato and Shih reported they worked backwards to replicate elements of human pathological aggression in mice, including low enzyme levels and the interaction of genetics with early stressful events, such as trauma and neglect during childhood.
“Low levels of MAO A are one basis of the predisposition to aggression in humans. The other is an encounter with maltreatment, and the combination of the two factors appears to be deadly: It results consistently in violence in adults,” Bortolato said.
The researchers showed that in excessively aggressive rodents that lack MAO A, high levels of electrical stimulus are required to activate a specific brain receptor, known as NMDA, in the prefrontal cortex. Even when this brain receptor does work, it stays active only for a short period of time.
“The fact that blocking this receptor moderates aggression is why this discovery has so much potential. It may have important applications in therapy,” Bortolato said.
The researchers are now studying the potential side effects of drugs that reduce the activity of this receptor.
“Aggressive behaviors have a profound socioeconomic impact, yet current strategies to reduce these staggering behaviors are extremely unsatisfactory,” Bortolato said. “Our challenge now is to understand what pharmacological tools and what therapeutic regimens should be administered to stabilize the deficits of this receptor. If we can manage that, this could truly be an important finding.”
The study appears in The Journal of Neuroscience.