Published online 6 November 2007 | Nature | doi:10.1038/news.2007.222

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Drug calms violent rats

Fixing a single neurotransmitter system suppresses pathological aggression.

Fight club: rats can be encouraged to be violent.Sietse F. de Boer

Researchers have found a drug that can reduce aggressive behaviour in feral rats that have been trained to be violent. Although the find may not lead directly to a cure for pathological violence in humans, it does unpick a mechanism behind such violence, the researchers say, which could open the door to future treatments.

Sietse de Boer and his colleagues from the University of Groningen in the Netherlands, who have developed the first animal model of pathological aggression, reported these findings at the Society for Neuroscience meeting in San Diego yesterday.

Although violence is a serious societal problem, until now scientists have only been able to study 'normal' or 'appropriate' aggression in animals — such as fighting over limited resources of food or mates. Such studies are usually done using normal laboratory rodents, which have been bred over the decades to be docile and easier for researchers to handle.

So the researchers decided to work with feral rats instead. Although a male rat will fight other males, it won’t attack females, preferring instead to court their sexual favours. It will also not fight with an anaesthetised 'intruder', recognising that it poses no threat. But de Boer was able to change this, training the rats to be gratuitously violent.

Angry rats

The team engendered violent characteristics by introducing feeble intruder rats that were bound to lose battles, each day for two or three weeks. After repeated victories over other rats, the test animals began to behave in a more pathologically violent manner, fighting all-comers more brutally — including weak females and senseless males which presented no threat to them.

Then de Boer looked at levels of the neurotransmitter serotonin in the rats’ brains. Low levels of serotonin are linked very strongly to aggressive behaviour, and pathologically violent people have been found to have lower levels of serotonin metabolites in their spinal fluid. Additionally, some antidepressants that increase serotonin levels have been seen to reduce violent behaviour in some people.

Although brain levels of serotonin don’t change in rats as a result of normal, 'appropriate' acts of aggression, de Boer found that these levels did sink in his pathologically aggressive rats.

Aggressive streak

The researchers also found that they could alter the aggressive behaviour of their rats by manipulating the serotonin system. They gave the rats S-15535, a compound that binds exclusively to a neuron 'autoreceptor' that acts to dampen the serotonin system. This autoreceptor is called 5-HT1a. Binding to it seems to bring serotonin levels in the rats back to normal.

When even very low doses of S-15535 were used to bind to the receptors, de Boer found that both the serotonin and the violence of the pathologically aggressive rats returned to normal levels. The much more limited violence of naturally low-aggression rats could also be brought back to normal by the compound — but only by using higher doses. The compound seems to work by ‘fixing’ the serotonin breaking system, which becomes dysfunctional in the super-aggressive rats, says de Boer.

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Unlike a tranquilizer, S-15535 didn’t make the rats lethargic or ‘spaced out’, it reduced their aggressiveness without affecting other behaviour.

No magic bullet

It is unknown whether S-15535 is a good drug candidate for pathologically violent people. "I can’t imagine that we can pin such a complex behaviour as pathological violence in humans on one single receptor," says de Boer.

But the study does prove that the serotonin system plays an important role in abnormally violent behaviour. And understanding the system is the first step to being able to control it, he points out.

Researchers at the European Molecular Biology Laboratory at Monterotondo in Italy have independently confirmed the importance of the 5-HT1a autoreceptor in aggression. At the same meeting, Enrica Audero and her colleagues reported results from experiments using their genetically modified mice, which can be made to overexpress the gene for this autoreceptor at any time. The group found that when they switched on this overexpression, the mice became more aggressive. When they switched it off again, the mice went back to normal behaviour.

"The two studies are pointing in the same direction," says Audero. 

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