Exposure to aggression may have lasting effects

By Beth Azar
Monitor staff

When rats or mice, and presumably men, fight, the experience actually alters the animals' brain chemistry at the genetic level, leads to drug tolerance and may promote addiction, explained Tufts University psychologist Klaus Miczek in his Master Lecture during APA's 1999 Annual Convention in Boston. Such findings may have important implications for research in humans by providing a possible link between drug abuse and aggression, and also by illuminating the influence environment has on shaping behavior.

Indeed, when Miczek and his colleagues examine the feedback loop between nurture and nature in aggressive interactions between animals, they find that defeated animals show signs of tolerance to morphine, before ever being exposed to the drug. They also discovered that levels of the neurotransmitters dopamine and serotonin rise and fall respectively in specific brain areas of victors and losers.

Although the significance for humans of all the changes remains to be discovered, the research shows that salient experiences can have long-lasting influences on brain and behavior.

The attacked...

Miczek described his work in the Aug. 20 lecture "Aggressive episodes' impact on amines and gene expression." He had observed that during and immediately after a confrontation in which a rat or mouse is defeated, the animal feels less pain than it did before the defeat. Days and weeks later, however, the animal becomes more sensitive to pain. When the researchers tested the animal's pain threshold by giving it a dose of morphine and then exposing it to heat, they found that blocking the pain required a higher dose of morphine than it did for undefeated animals, said Miczek. This is akin to what researchers see when animals become tolerant to morphine. When they're exposed to morphine over a period of time, it begins to lose its effect and they need a higher dose to block the same amount of pain. In essence, the defeated animals in Miczek's study develop morphine tolerance without ever having had any drug. They also develop withdrawal symptoms if researchers inject them with a drug that blocks the effect of morphine.

"You can show tolerance and withdrawal in animals who have never seen a drug, but who have a powerful salient experience," said Miczek. In fact, animals don't have to be attacked to show this effect, he said. Just the threat of confrontation is needed.

Armed with these behavioral findings, Miczek and his colleagues examined the defeated animals' brains to explore what might be occurring on a molecular level. They found that during an attack and just after a defeat the animals are less sensitive to pain. When they looked at the animals' brain tissue half an hour after a defeat or the threat of defeat, they found a doubling and tripling of the expression of an immediate early gene called c-fos--one of many genes known to initiate protein production in cells.

In some of the same brain areas where c-fos is turned on, researchers found evidence that cells are actively producing proteins for an opiate receptor called mu, indicating that they're upping their natural number of these receptors. This may be one way animals become immune to pain during defeat. Other studies indicate that animals without this receptor gene get no pain relief from morphine.

"Something is really happening in the brain as a result of one single significant experience," said Miczek. "These changes are not only large, long-lasting and specific to certain areas of the central nervous system, but these changes are important behaviorally for issues of tolerance and drug abuse."

In fact, along with tolerance to morphine, an opposite effect takes place. Defeated animals become more sensitive to other drugs, such as cocaine.

"So here we have completely divergent processes in the central nervous system," explained Miczek. "One, tolerance, a form of neuroadaptation, and the other, sensitization, occurring roughly in the same timeframe."

In addition, he said, defeated animals learn to self-administer cocaine roughly twice as fast as undefeated animals.

...and the attacker

The attacking animal isn't immune to these types of central nervous system changes, explained Miczek. He and his colleagues are using a new technique to look at changes in the brain as they occur. By sticking tiny capillary tubes into rats' brains, they can measure the chemicals active in the brain as the rat moves about. Dopamine and serotonin are of particular interest because high levels of dopamine and low levels of serotonin have been associated with aggression in animals and humans.

The study begins with a rat that has no experience with aggression. During its first fight as attacker and winner, there's no change in dopamine levels. But after the fight, there is a drop in serotonin levels in the rat's cortex. To see whether long-term experience with fighting would change the rat's brain chemistry, Miczek and his colleagues allowed the rat to fight every day for 10 days at precisely the same time. On the 11th day the animal didn't fight, but the researchers measured its brain chemicals. They found that in anticipation of an imminent fight, dopamine levels increased and, as seen before, serotonin levels decreased, despite the fact that the animal never fought.

In a sense, experience changed the animal's brain chemistry and geared it up for a fight, said Miczek. This line of research provides an important message about the role of experience in shaping behavior

"Salient experiences, defeat experiences, aggressive experiences, single experiences, can result in large, long-lasting and consequential changes," he said. "Within a few minutes, genetic expression can be set into motion and it can be very important for such fundamental processes as neuroanatomical changes involving [drug] tolerance, sensitization resulting in higher drug taking, preparing for fights and stress-related diseases."



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