Brain Chemicals Involved In Aggression Identified: May Lead To New Treatments

And new studies are helping scientists gain deeper insight into the neurobiology of aggression and violence. One analysis of brain imaging studies has revealed that brain structures involved in making moral judgments are often damaged in violent individuals. Another study involving teenage boys suggests that disruptions in a brain region linked to impulsive, aggressive behavior may underlie a certain type of violent, reactive behavior.

Still other research has shed new light on the role that certain brain chemicals play in aggressive behavior, including in maternal aggression. And new animal studies reveal that aggressive encounters cause changes in the brains of aggressors as well as their victims that increase vulnerability to depression and immune-related illnesses.

"Violence in our society is a major concern, indeed, a national health problem," says Craig Ferris, PhD, of Northeastern University in Boston. "Understanding the confluence of events, both environmental and biological, that trigger a violent act has been the focus of educators, health professionals, and scientists for decades.

"New imaging technologies and animal models have helped neuroscientists identify changes in brain neurobiology associated with inappropriate aggressive behavior," he says. "This information may help in the development of new psychosocial and psychotherapeutic intervention strategies." Ferris is a stockholder in Azevan Pharmaceuticals, which is developing drugs to stop self-injurious behavior.

After analyzing data from 47 independent brain imaging studies, researchers at the University of Pennsylvania have found that the rule-breaking behavior common to people with antisocial, violent, and psychopathic tendencies may result partly from damage to the neural circuitry in the brain that underlies moral decision-making.

"This finding supports other studies that may force society to question its attitude toward the nature of crime and punishment," says Adrian Raine, PhD. "For example, should psychopaths be punished if, for reasons beyond their control, they do not have the appropriate brain circuitry to process moral dilemmas?"

Scientists have long known that damage to certain regions of the brain, most notably the prefrontal cortex, can result in violent behavior. More recently, imaging studies have identified the neural circuits that become activated in the brains of normal, healthy individuals during moral decision-making.

The analysis was undertaken to see if the brain regions compromised in antisocial populations include the newly identified brain regions involved in moral decision-making. Raine and his colleagues compared the brain images of 792 antisocial individuals with 704 control subjects. They found that antisocial individuals also tended to have overlapping damage in brain structures involved in making moral judgments, most notably the dorsal and ventral prefrontal cortex, the amygdala, and the angular gyrus.

"If offenders are not fully responsible for the source of the brain dysfunction that impairs their moral-decision making, this raises a significant neuroethical issue regarding the appropriate level of punishment for those who perpetrate morally inappropriate acts," Raine says.

New studies from the University of California, San Diego, are helping scientists better understand what goes on in the brains of some teenage boys who respond with inappropriate anger and aggression to perceived threats. Preliminary findings from these studies suggest that such behavior is associated with a hyperactive response in the amygdala, an area of the brain that processes information regarding threats and fear, and with a lessening of activity in the frontal lobe, a brain region linked to decision-making and impulse control.

"This work will provide significant neurobiologic insight into why some adolescents become aggressive and violent," says Guido Frank, MD. "Eventually, it may lead to more effective therapies for helping adolescents overcome excessively aggressive behaviors that are harmful to themselves as well as to others."

Aggressive behavior can be divided into two types: proactive and reactive. Proactive aggressors plan how they're going to hurt and bully others. Reactive aggression, however, is not premeditated; it occurs in response to an upsetting trigger from the environment.

"Reactively aggressive adolescents -- most commonly boys -- frequently misinterpret their surroundings, feel threatened, and act inappropriately aggressive," Frank says. "They tend to strike back when being teased, blame others when getting into a fight, and overreact to accidents. Their behavior is emotionally 'hot,' defensive, and impulsive."

The term "reactive-affective-defensive-impulsive" (RADI) has recently been created to describe such behavior. Research suggests that adolescents with RADI behavior are at an increased risk for a lifetime of problems associated with impulsive aggression. "A major problem in researching this topic is stigma and a notion that children will grow out of aggressive behaviors," Frank says. "It's often difficult to recruit such youngsters and their families to participate in research."

Little is known about how the brain works in reactive aggression. In their most recent studies, Frank and his colleagues recruited two groups of male adolescents: one group diagnosed with RADI behavior and the other group without any history of mental illness or aggression problems. While being scanned by a brain imaging machine, both sets of teenagers were asked to perform tasks that involved reacting to age-appropriate, fear-inducing images. The tasks also tested the teenagers' impulsivity.

Preliminary data reveal that the brains of RADI teenagers exhibited greater activity in the amygdala and lesser activity in the frontal lobe in response to the images than the brains of the teenagers in the control group. In a related study, Frank and his colleagues are investigating whether these changes in brain activity are associated with an abnormal increase in cortisol levels, a marker of the stress response.

The brain chemical serotonin has long been known to play an important role in regulating anger and aggression. Low cerebrospinal fluid concentrations of serotonin have even been cited as both a marker and predictor of aggressive behavior.

New studies from the Netherlands, however, indicate that this serotonin-deficiency hypothesis of aggressiveness may be too simple. "Serotonin deficiency appears to be related to pathological, violent forms of aggressiveness, but not to the normal aggressive behavior that animals and humans use to adapt to everyday survival," says Sietse de Boer, PhD, of the University of Groningen.

Furthermore, research now suggests that unchecked aggressive behavior can eventually change the brain in ways that cause serotonin activity to decrease-and, perhaps, violent behavior to increase.

To perform their most recent studies, de Boer and his colleagues engendered violent characteristics of aggressive behavior in feral mice and rats by permitting them to physically dominate other rodents repeatedly. With such positive reinforcement, the animals' initially normal aggressiveness gradually became transformed into a more pathological form-the kind also seen in pathologically violent people.

During this transformation, de Boer studied the chemical changes that occurred in the rodents' aggression-related brain circuits, particularly those circuits involved with serotonin. They found that serotonin activity decreased as a result of the animals experiencing repeated victorious episodes of aggression but not as a result of normal, functional acts of aggression.

"Our findings support meta-analyses of serotonin activity in aggressive humans," says de Boer. "That data showed that serotonin deficiency is most readily detected in people who engage in impulsive and violent forms of aggressive behavior rather than in individuals with more functional forms of aggression."

More recently, de Boer and his colleagues have found that the transition from normal, adaptive aggressive behavior into abnormal forms that inflict harm and injury is due to functional, but not structural, changes in certain serotonin receptors in the brain. In animal studies, treatment with selective serotonin receptor agonist compounds has been found to restore the normal function of these receptors-and suppress aggressive behavior, including its escalated forms. These findings may one day lead to more effective treatments for violent behavior in humans.

Researchers have identified, for the first time, that the release of a neurotransmitter called arginine-vasopressin (AVP) in an area of the brain called the amygdala helps regulate maternal aggression-a behavior that ensures the survival of the offspring. Although the study was conducted using rat dams, maternal aggression occurs in all mammals, including humans.

"By understanding the brain pathways underlying maternal aggression in rodents, we're also gaining deeper understanding of regulation of maternal behavior in general," says Oliver Bosch, PhD, of the University of Regensburg, in Germany.

Much of the past research into the neurobiology of maternal aggression has focused on oxytocin, a neurotransmitter released in the brain during birth and breastfeeding. Oxytocin reduces anxiety and fear, a factor that is believed to enable new mothers to more aggressively face intruders that might harm their offspring.

In his new study, Bosch investigated whether AVP also plays a role in the regulation of maternal aggressiveness. Found in all mammals, AVP is synthesized in the brain and then released to the kidneys, where it helps regulate the body's retention of water. More recently, AVP has been implicated in male aggression and other social behavior, particularly pair-bonding between sexual partners.

Using tiny probes that enabled the real-time collection of samples of brain fluid, Bosch and his colleagues measured the release of AVP within the amygdala, an area of the brain associated with both maternal anxiety and aggression, while rat dams moved around their cages with their pups. Some of the dams had been selectively bred for high anxiety-related behavior; others had been bred for low anxiety-related behavior. High-anxiety dams are not only more anxious, but also show more maternal aggression towards intruders. In addition, they spend more time nursing and in direct contact with their pups.

During the study, the rat dams were sometimes left undisturbed and were at other times confronted for 10 minutes with an intruder. The more aggressive, high-anxiety dams released more AVP within the amygdala while defending their offspring from the intruder than did the less aggressive, low-anxiety dams-a finding that strongly suggests a role for AVP in maternal aggression.

The researchers also found they could use the brain's AVP system to manipulate the aggression shown by the dams. When the animals were given an AVP receptor antagonist, which blocks the brain's receptors for AVP, the dams became less anxious and less aggressive. When synthetic AVP was infused into the animals' brains, however, the dams became more anxious and increasingly aggressive.

"While AVP's effects on maternal aggression are similar to what we found earlier for oxytocin, these neuropeptides act differently on anxiety," Bosch says. "So it's the brain's AVP system itself, not AVP acting on oxytocin receptors, that causes these changes in maternal behavior."

Being the recipient of an aggressive social encounter can cause changes in the brain that lead to depression, anxiety, and susceptibility to immune-related illnesses, according to new animal studies from Carleton University in Ottawa. Surprisingly, some of these negative effects appear to be as strong in animals that successfully dominate social situations as in those that react with submission.

"It seems that aggression, which is clearly deleterious to the well-being of the victim, also has several negative repercussions for the aggressor as well," says Marie-Claude Audet, PhD.

Social stressors and negative relationships are believed to contribute to stress-related disorders, including depression and anxiety. Stressful events have a profound influence on the neuroendocrine and neurochemical systems, causing chemical changes in many areas of the brain, including several that are strongly involved in emotions: the prefrontal cortex, the hippocampus, and the amygdala. Among the neurotransmitters and hormones altered by stress are dopamine, serotonin, noradrenalin, and corticotropin-releasing hormone (CRH) (which affects blood levels of corticosterone). Recent research also has suggested a link between stress and cytokines (signaling molecules within the immune system). Cytokines may inform the brain of the presence of pathogens in the body, thus triggering a stress-like response.

To more precisely determine how a social stressor disturbs neuroendocrine, neurochemical, and cytokine function as well as behavior, Audet and her colleagues designed a study in which naive mice (ones not previously exposed to any social situation) were introduced to the home cage of dominant mice for 15 minutes on either a single day or on three consecutive days. As a control, some mice were not exposed to any social stressor. The animals' basal motor activity was monitored, and blood and brain samples were taken and analyzed either 3 minutes or 75 minutes after the end of the stressor.

The study found that aggressive social interactions caused both dominant and submissive mice to become hyperactive relative to the controls. However, although motor activity remained high in dominant mice, particularly in those that engaged in vigorous behavior, it declined gradually in the submissive mice. Corticosterone levels-a marker of stress-were significantly increased soon after the end of the stressor session, and those levels remained elevated for protracted periods over the course of the experiment. The increase was similar in both submissive and dominant mice. Some cytokines also became elevated in the prefrontal cortex of both groups of mice, and this effect was greater after the stressful social encounters were repeated.

Measurements of stress-related neurotransmitters and hormones, however, revealed some significant differences between the dominant and submissive animals. For example, brain levels of the neurotransmitter noradrenaline, which may help mediate the effects of stress on the body, fell in the hippocampus of the dominant mice, but increased in the central amygdala of the submissive mice. The expression of CRH also fell in the prefrontal cortex of the dominant mice, but only after repeated encounters with an intruding mouse.

In further studies, Audet observed that chronic exposure to social stress increased the sensitivity to a bacterial challenge and that this effect was more apparent in dominant mice.

"Our findings suggest that stressful social experiences, by affecting central neurotransmitters and cytokines, may influence vulnerability to depression and susceptibility to immune-related illness," says Audet. "Moreover, it appears that in addition to markedly affecting the victim's existence, aggression may have detrimental consequences also for the one that dominates the interaction."