C&EN: SCIENCE & TECHNOLOGY - A Recipe For Violence

A RECIPE FOR VIOLENCE

Potent mix of brain chemistry, brain damage, genetics, and environment leads to aggression

SOPHIE L. WILKINSON , C&EN WASHINGTON


HOOLIGANS Soccer fans' violence stems from a multitude of factors.
NEWSCOM/KIERAN DOHERTY

It's not just pop psychology: along with the targets of their actions, violent and aggressive people are victims, too.

Although people are ultimately responsible for their own actions, their predilection for violence is shaped by the complex interplay between their genetic inheritance and the physical and psychological environment of their formative years and beyond. In addition to genetic defects, risk factors include child abuse, exposure to lead, alcohol abuse, and accidental brain damage. These negative influences can be ameliorated by protective genes, good parenting, and pharmacological intervention.

Chemists, medical professionals, sociologists, and others are teasing apart the threads that make up this messy tapestry of cause and effect in order to improve treatment of offenders and reduce the incidence of violence.

The need is great. Despite a downward trend in the past few years, 1.4 million violent crimes were committed in the U.S. in 2000, according to the Bureau of Justice Statistics. The National Center for Health Statistics reports that homicides totaled 16,765 that year and 29,350 people committed suicide.

Of course, these statistics exclude a wide range of actions that don't meet the definition of a violent crime or that go unreported. Examples include socially sanctioned violence, such as a hockey brawl, and illness-related aggression toward a caretaker, such as that caused by Alzheimer's disease.

There are, in fact, multiple kinds of aggression or violence that can be categorized in numerous ways. One common division separates premeditated aggression–such as the 1999 Columbine High School massacre–from impulsive, unplanned aggression, which usually occurs in response to a frustrating or irritating stressor.

Researchers realized two decades ago that violent behavior was associated with flaws in the serotonin neurotransmitter system–but only in impulsive aggressive people, explains Emil F. Coccaro, director of the Clinical Neuroscience & Psychopharmacology Research Unit at the University of Chicago. Most of the early research into the biochemistry of violence thus centered on impulsive aggression, and that allocation of resources continues to this day. But just because serotonin does not appear to be involved in planned violence, Coccaro is quick to note, "that does not mean there isn't a biology to premeditated aggression."

Serotonin, also called 5-HT, is primarily an inhibitory neurotransmitter that acts as a kind of brake on impulsiveness. Individuals with normal or higher levels of serotonin show more restraint and think things out, says J. Dee Higley, a research psychologist at the National Institute on Alcohol Abuse & Alcoholism (NIAAA). Those with low serotonin levels, on the other hand, "act first and think later, and that gets them in trouble."

BUT IMPULSIVE BEHAVIOR isn't all bad. "Under certain settings, impulsiveness probably pays a benefit," Higley says. In war, for instance, it may require an impulsive person to succeed at a daring charge to take the top of a hill. Likewise, explorers and settlers may also be impulsive characters who are willing to take risks.

"The problem is if you're impulsive and you have a short fuse, and you get into a setting that's likely to elicit violence, you are going to be more prone to exhibit aggressive behavior," Higley says.

Consider a man who goes into a bar and sees his girlfriend chatting with another man. If the boyfriend suffers from impaired serotonin function, he may "impulsively jump right in, ending up in an altercation and perhaps some sort of fracas," Higley says. But if the boyfriend's serotonin system functions well, he may eye the stranger and say, "Hey, he's got a beer bottle in his hand. He's bigger than me. Maybe I'll wait and talk about this later on with my girlfriend."

Although serotonin appears to be the major neuro-transmitter involved in aggression, it's not the only game in town.

Higley has devoted more than 25 years to the study of violence, working for the past 15 years with a colony of about 5,000 free-ranging rhesus monkeys that live on a South Carolina island. He gauges serotonin system function by periodically taking a little cerebrospinal fluid (CSF) from the monkeys and measuring levels of 5-hydroxyindoleacetic acid (5-HIAA), a serotonin metabolite.


MONKEY BUSINESS South Carolina monkey colony studied by Higley shows link between serotonin levels and aggression.
PHOTO COURTESY OF J. DEE HIGLEY

Levels of 5-HIAA, which remain consistent over the years in individual monkeys, confer a "personality style" on each animal, Higley says. Those with low 5-HIAA–and presumably with impaired brain serotonin systems, he says–sport more scars and wounds. Although other monkeys in the colony are just as likely to initiate aggression, the low-5-HIAA monkeys tend to escalate an incident out of control. What "starts off as a play bout or a mild tussle over a piece of chow escalates to where the monkeys are jumping through the trees or rolling around biting each other–both of which are pretty high-risk kinds of violent behavior," he says.

Even when the low-5-HIAA monkeys aren't having tantrums, they are daredevils. Typical monkeys move throughout the island by way of the treetops, which are 10 to 20 meters high, by carefully pulling a branch over to cross to the next tree or by retreating if they can't find a reasonable route. The low 5-HIAA monkeys are not deterred by a gap between trees; they just spontaneously leap from one to the next. The performance is "stunning to watch, but very dangerous to the impulsive monkey," Higley says.

THESE SEROTONIN-impaired monkeys also show marked behavioral differences during a test in which the animals can access food but end up in a trap from which they cannot escape. After going through this experience, many monkeys avoid the setup for a year or two. However, the low-5-HIAA monkeys repeatedly return for food despite the trap, sometimes on successive days.

Results with the monkeys are borne out by human behavior. Higley's NIAAA colleague, the late Markku Linnoila, studied arsonists and found that those who committed the crime impulsively had low serotonin. On the other hand, those who did it for pay had normal levels of 5-HIAA. Linnoila also studied prisoners who had committed impulsive, violent crimes. He found that "the more violent they were, the more times they had acted aggressively throughout their lives, the lower the 5-HIAA that they had," Higley says.

Coccaro has also been studying the human serotonin system for years. In his early work, he looked at patient response to a drug, fenfluramine, that increased serotonin activity in the brain.

Patients who were more aggressive showed a lower response than the less aggressive patients, presumably because the more aggressive patients' serotonin systems were less active. And people with a history of suicidal behavior also showed a lower response, "because the serotonin system relates both to aggression directed outwardly and aggression directed inwardly," he says. Coccaro notes that brain serotonin levels are lower in those who commit suicide as compared to those who die violently by other means.

In a subsequent study, Coccaro attempted to boost patients' serotonin levels by decreasing the

neurotransmitter's reabsorption by neurons. In this work, he compared the selective serotonin reuptake inhibitor Prozac (fluoxetine) and a placebo in patients with impulsive aggressive personality disorder–"people who are hotheads."

Coccaro found that some of the Prozac recipients improved. And when he recently reanalyzed the results of that study, he discovered that "the improvement was entirely in people who were moderately aggressive." Unlike those patients, Coccaro reasoned, their more aggressive fellows had such damaged or poorly functioning serotonin systems that a drug such as Prozac couldn't help.

Anticonvulsants that can also be used as mood stabilizers are an alternative treatment. Coccaro plans to compare Prozac and the mood stabilizer Depakote (divalproex sodium) in the treatment of moderately aggressive patients. These drugs may work by a different enough mechanism that they could even be used to treat the more violent patients, he says.

Although the mechanism isn't fully understood, Depakote is known to increase brain levels of -aminobutyric acid, an inhibitory neurotransmitter. It also may increase serotonin activity through a different mechanism than Prozac does, Coccaro says.

Dilantin (phenytoin), an anticonvulsant used to treat epilepsy, cut the number and intensity of aggressive acts committed by impulsive convicts, according to a study by Ernest S. Barratt, a professor in the psychiatry and behavioral sciences department at the University of Texas Medical Branch in Galveston. But the drug had little effect on those who committed premeditated aggression.

The anticonvulsant carbamazepine and the mood stabilizer lithium may also prove helpful in reducing violent behavior. Carbamazepine's activity isn't clearly understood. But lithium is believed to boost serotonin levels.

Although serotonin appears to be the major neurotransmitter involved in aggression, it's not the only game in town. Coccaro found a positive correlation between a life history of aggression and elevated levels of the neurotransmitter vasopressin in the subject's CSF. There is also evidence that high levels of norepinephrine and dopamine are positively related to aggression, he says.

HORMONES MAY also be a factor, although their impact is unclear. Coccaro, for instance, has not found a link between levels of the steroid hormone testosterone and aggression.

In his own studies, Higley says monkeys with high testosterone levels "were more likely to act competitively, but they were no more likely to act in a violent manner" than monkeys with lower testosterone levels. But low levels of 5-HIAA mixed with high levels of testosterone created "the worst characters in the whole study. These are the guys who were chronically in trouble and tended to act aggressively in a wide variety of settings and in unrestrained fashion," Higley says. These results suggest "that testosterone is the push to act in an aggressive manner, but the brakes that control the setting, to whom, and the level that you're going to express it at are based in the serotonin system."

Armed with new understanding of the role of neurotransmitters and hormones in aggression, the medical profession can apply treatments that

compensate for flaws in these biochemical systems. Eventually, it may even be possible to fix underlying genetic faults. But that's a long-term goal. For now, "we know very little about the identity and function of specific genes that contribute to the risk for violent behavior," says Evan S. Deneris, associate professor of neuroscience at Case Western Reserve University School of Medicine, Cleveland. "So it's pretty foggy."

Deneris and his colleagues are trying to pierce that fog by identifying which genes are important in the development of the brain's serotonin neurons. They discovered a gene, designated Pet-1, that proves to be critical for the development and proper function of serotonin neurons. In mice that are genetically engineered to lack this gene, brain serotonin levels are only 1015% of the normal level [Neuron, 37, 233 (2003)]. As expected, Deneris says, the knockout mice exhibit heightened aggression and anxiety.

Mouse aggression can be gauged by how staunchly males defend their territory. A "resident mouse" in its home cage will become perturbed if another male mouse–the "intruder" –is introduced into the cage, Deneris says. A wild-type resident mouse "will go up to the intruder, sniff it, groom it, and eventually may even attack the intruder by biting it, chasing it around the cage, and trying to get it out. So typically, there's a period of nonaggressive curiosity that can be followed by physical attack," Deneris says. The resident mouse "is being cautious about what it's doing. It's not being impulsive."

Deneris measured the time it took for wild-type resident mice to attack intruder mice. Then he measured this "attack latency" for his Pet-1 knockout resident mice. "Our knockout mice spend a lot less time in nonviolent, exploratory behavior," he says. "They're very impulsive, and oftentimes they don't spend any time exploring. They don't spend any time thinking about what they're doing. They just go straight for the intruder and start to attack it." In addition, the knockout mice carry out more attacks and more severe attacks than the wild-type mice.

"Our findings identify the first gene that impacts aggressive behavior in the adult through control of fetal serotonin neuron development," Deneris says. "The goal now is to determine the mechanisms through which the Pet-1-dependent genetic program regulates serotonergic modulation of aggression." He also plans to study "what has happened to the rest of the brain in the face of this low level of serotonin. Have the postsynaptic targets of serotonin neurons modulated themselves by either increasing or decreasing receptor expression?" That's not a simple question, given that the brain has more than a dozen types of serotonin receptors.

The human and mouse serotonin systems share many features, and the same Pet-1 gene is present in the human genome. Thus, Deneris also wants to find out whether the human version of Pet-1 performs a similar function and whether naturally occurring genetic variants of the Pet-1 program exist and contribute to the risk for aggressive behaviors.


	Normal	Murderer
	ACTIVITY DEFICIT Raine's PET scans show greater activity (red regions) in the prefrontal cortex of a normal brain than in a murderer's brain. IMAGES COURTESY OF ADRIAN RAINE

Researchers are studying the role of other genes as well. For instance, knockout mice lacking the gene for neuronal nitric oxide synthase, an enzyme involved in neurotransmission and production of nitric oxide, are extremely aggressive. In studying these mice, Randy J. Nelson, a social and behavioral sciences professor at Ohio State University, and colleagues concluded that "neuronal-derived NO is essential to the normal function of the central 5-HT system."