‘Cuddle hormone’ oxytocin inhalation turns aggressive rat into social cage companion

Extremely aggressive rats start to behave normally after treatment with the ‘cuddle hormone’ oxytocin, concludes behavioural physiologist Federica Calcagnoli in her PhD research. Remarkably, administering oxytocin via the nose is just as effective and selective as direct injection into the brain. This indirect administration route is a very promising starting point for anti-aggression medication. Calcagnoli was awarded a PhD by the University of Groningen on 13 October.

It has been known for decades that oxytocine is the hormone that stimulates lactation and uterine contractions. In recent decades, scientists have also seen oxytocin as an important messenger in the brain for social behaviour. When cuddling, for example, oxytocin levels in the brain rise and the substance also strengthens parental behaviour and pair-bonding.

Normal rats

Taking this as a starting point, researchers have suggested that oxytocin may also reduce aggression. However, there was never any definitive proof of this. Standard laboratory rats are rarely aggressive, which complicates research on such effects. Federica Calcagnoli thus conducted her aggression experiments on rats with a normal aggression pattern.

Invader test

In order to investigate whether oxytocin really does reduce aggressive behaviour, Calcagnoli used the ‘invader test’: a male rat, the ‘cage owner’, is confronted in his own territory with an unknown male rat, the invader. Aggressive animals then threaten and fight. Calcagnoli then administered oxytocin directly into the amygdala of the rat brain – that part of the brain involved in social behaviour and emotions – via a subcutaneous pump. Animals that initially reacted aggressively to their invader grew calm and even began to display social behaviour towards the newcomer. Not only that, the changes turned out to last for a long time – for at least a week after the experiment.

Intranasal

As well as the direct route, Calcagnoli also administered the oxytocin via the nose. To her surprise this method turned out to work as well as direct administration to the brain. Previous studies of animals and humans had already shown that oxytocin levels in the brain rise after intranasal administration. This is remarkable because it is highly unlikely that a substance administered nasally goes directly to the brain. Calcagnoli demonstrates that oxytocin administered nasally induces oxytocin production in the brain. How this occurs exactly is not yet clear.

Extreme aggression

Calcagnoli also demonstrated that extremely aggressive behaviour is linked to low oxytocin production in the brain. This link has also been found in humans. In order to replicate an extreme degree of aggression, she let a number of animals repeatedly win in mutual conflicts. Some of the rats developed pathologically aggressive behaviour as a result – they attacked females and anaesthetized animals and immediately started fighting without first threatening. Analysis of their brain tissue confirmed a low oxytocin transcription.

Temper tantrums

‘The fact that oxytocin selectively reduces aggression and stimulates normal social behaviour is an important finding’, explains Calcagnoli’s co-supervisor Sietse de Boer: ‘Uncontrolled aggressive outbursts and antisocial behaviour are a growing problem in society, for example in autism and schizophrenia, but also in elderly people with Alzheimer’s or other neurodegenerative brain diseases. Temper tantrums are often a problem not only for the carer but also the patient.’

Selective aggression medicine

‘The oxytocin system in the brain appears to be an attractive starting point for the development of effective medication precisely because it shifts specific aggressive behaviour towards social behaviour, with no side effects. The drugs on the market at the moment have an awful lot of side effects, which blunt people’s social interactions. Nasal administration is also relatively simple.’

Curriculum Vitae

Federica Calcagnoli (Italy, 1986) studied pharmacy at the University of Camerino in Italy. She conducted her PhD research at the Centre for Behaviour and Neurosciences (CBN) of the University of Groningen. The research was partly funded by a grant from the Ubbo Emmius Fund of the University of Groningen. Her primary supervisor was Prof. J.M. Koolhaas and her co-supervisors were Dr S.F. de Boer and Dr M. Althaus. The title of her thesis is: Oxytocin: the neurochemical mediator of social life. The PhD defence ceremony was held on Monday 13 October 2014.

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Co-promotor Dr Sietse F. de Boer