Anticipating aggression changes brain chemistry, researchers find
by Marjorie Howard

Serotonin is a substance in the brain that regulates many functions, including sleep, mood and appetite. During the last 30 years, research on serotonin has led to the development of new drugs that treat a range of diseases, including depression, anxiety, obsessive compulsive disorders, hypertension and migraines. Probably the best known drug that regulates serotonin is the popular anti-depressant Prozac.

Klaus Miczek © Mark Morelli

But all these medications affect serotonin levels after the fact—that is, after a person experiences problems. What if a drug could be created that prevents the problem from occurring in the first place?

Klaus Miczek, the Moses Hunt Professor of Psychology, and a team of researchers in his laboratory have devised a novel way of showing that changes in the levels of chemicals in the brain do not necessarily precede behavioral changes. Instead, they found that changes in serotonin and dopamine, two neurochemicals thought to cause aggressive behavior, are a consequence of such behavior.

Fighting off the intruder
What Miczek and his colleagues did was to use laboratory rats in an unusual experimental protocol. When a rat is placed into the cage of another rat, the "resident" rat will attack the "intruder." Each day at the same time, Miczek's lab placed an intruder rat into the cage of a resident rat, and the rats fought. In one set of animals, dopamine and serotonin levels were measured before, during and after the very first fight. The procedure was repeated for 10 days. On the eleventh day, no intruder rat was brought in. Nevertheless, in anticipation of the fight, the resident rat's serotonin dropped and dopamine levels rose prior to the time when fighting had occurred during the previous 10 days.

"The reigning theory is that some deficit in serotonin predisposes an individual to be more violent," said Miczek. "We show that changes in serotonin not only occur when there is a fight but when there is the anticipation of fighting. The change in neurochemistry is not the causative event but the consequence. It's fascinating because it tells us that at the molecular level, neurochemical changes occur that are subject to conditioning.

"If one extrapolates from the laboratory to the real world of conflict, it is tempting to speculate that one could develop diagnostic tools to identify those individuals who are most intensely affected by an imminent confrontation," he said.

Motivated behavior
The research focused on a part of the brain called the nucleus accumbens, which is in the forebrain and can be seen in humans with neuro-imaging techniques. According to Miczek, conditions such as drug abuse, schizophrenia and overeating, as well as many other behaviors, are linked to activity in the nucleus accumbens. This part of the brain "is fundamental to voluntary, motivated behavior," he explained.

In what Miczek described as a technical tour de force, his lab devised a way to measure the serotonin and dopamine activity of brain cells directly in the nucleus accumbens while other physiological and behavioral events were also being measured. Most research, he explained, is retrospective—that is, it looks at a process after a critical event has occurred. In this case, Miczek and his lab studied the chemical changes taking place while the behavior was going on by using a specially developed probe.

"The animals were in an intense fighting episode," he explained. "We had placed a delicate probe in their brains that allowed us to sample brain cell activity every few minutes while the fighting was going on. The rats were also fitted with a sender in the belly that transmits heart rate and temperature. Measuring all of these activities while the action is taking place has never been done before." Not only did the probe go into the brain, but the researchers were able to target the exact part of the brain they wanted to study.

Miczek pointed out that it is possible to study "such a complicated process as anticipation" only in a laboratory setting using laboratory animals. "It would be inconceivable to study this in a human," he said, noting it would be "unthinkable" to have a human commit a violent act for an experiment.

Serotonin controls
One of the next questions the researchers want to answer is what is controlling the drop in serotonin? "If a serotonin deficit is not the causative factor," Miczek said, "then what is? What are the events that influence the serotonin change? There may be therapeutic targets we don't know about. Prozac targets serotonin, but that's after the fact. What we would like to do is learn how we can anticipate the change in the level of neurochemicals and what can we do before that level changes."

Miczek said he and his colleagues also want to study a different part of the brain, the prefrontal cortex, which has long been implicated in impulsivity and violent outbursts. The other investigators in the experiment were Pier Francisco Ferrari, a postdoctoral fellow; A.M.M. van Erp, a research assistant professor who devised the brain probe, and Walter Tornatzky, a research assistant professor who was responsible for the heart rate and temperature measurements.