Blocking Dopamine Has Unexpected Effect on Aggression in Mice

In a breakthrough that could one day help individuals with pathological aggression, researchers at Columbia University identified a specific receptor related to the neurotransmitter dopamine that could be targeted with drugs to help manage this aberrant behavior.

The researchers, who examined the role of dopamine in the lateral septum of mice, published their findings online Nov. 23 in the journal Nature Communications.

To conduct the study, the researchers first applied a manipulation to increase the release of dopamine from its endogenous pools within the lateral septum during social interaction, leading to an increase of aggressive behavior in the mice. But when they inhibited dopamine release, aggressive behavior ceased.

"We reasoned that by identifying the dopamine receptor responsible, we could test drug treatments on aggression," said Rinki Saha, PhD, a post-doctoral research in neuroscience at Columbia University Irving Medical Center, who co-led the study along with Darshini Mahadevia, PhD, also a post-doctoral research scientist at CUIMC.  "Indeed, we found that blocking D2 receptor function in the lateral septum reduced aggression.”

The lateral septum region of the brain is essential for regulating aggressive behavior. While it receives strong dopamine input, if and how these dopamine pathways influence neural circuits and behavior has largely been unknown.

The researchers used optogenetics—which employes light to stimulate or inhibit activity in neurons—to learn how a specific dopamine pathway that targets the lateral septum influences neuronal communication and behavior in the mice. They found that when more dopamine was released, neurons in the lateral septum were inhibited and aggressive behavior was increased. When the pathway was blocked, aggressive behavior was reduced, demonstrating that dopamine release in the lateral septum is not only sufficient to trigger aggression, but also necessary for normal agonistic behavior.

“By discovering that dopamine regulates the activity of neurons in the lateral septum, we effectively link the classic septal-hypothalamic aggression axis with the clinically pertinent dopamine model of aggression,” said Mark Ansorge, assistant professor of clinical neurobiology (in psychiatry) and senior author of the study. “The principal role of the septal-hypothalamic pathway in aggression was identified almost a century ago, work for which Walter R. Hess received the 1949 Nobel Prize in Physiology or Medicine.”

Dr. Ansorge said that in the clinic, dopamine-related drugs are used manage aggression, but how and where in the brain they act is not known. In particular, one theory posits that they work by inducing sedation. The researchers’ findings now imply that blocking D2 receptors within the lateral septum can directly reduce aggression.

“Through this insight we hope to improve treatment approaches for pathological and displaced aggression, in order to help affected individuals and families with related brain disorders, such as schizophrenia, substance use disorders, and dementia.”

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