Oxytocin, the warm, fuzzy miracle hormone that promotes feelings of love, social bonding and well-being, isn't quite as simple as those miracle-cure-of-the-week newspaper stories want you to believe.

It turns out that correlation is not causation, which surprises no one in science, and that oxytocin is also linked to emotional pain. Maybe someone will call this other form Dark Oxytocin, because stressful social situations continue to haunt you and and even trigger fear and anxiety in the future, you can blame hormones. And putting Dark in front of mysterious things is popular.

Oxytocin strengthens social memory in the lateral septum region of the brain, researchers in a new paper say, by triggering a signaling molecule - ERK (extracellular signal regulated kinases) - that becomes activated for six hours after a negative social experience. ERK causes enhanced fear, they say, by stimulating the brain's fear pathways, many of which pass through the lateral septum.

The authors believe their findings are important because chronic social stress is one of the leading causes of anxiety and depression. This study in mice is particularly relevant because oxytocin currently is being tested as an anti-anxiety drug in several clinical trials.

"By understanding the oxytocin system's dual role in triggering or reducing anxiety, depending on the social context, we can optimize oxytocin treatments that improve well-being instead of triggering negative reactions," said Jelena Radulovic, the senior author of the study and the Dunbar Professsor of Bipolar Disease at Northwestern University.   

They say this is the first study to link oxytocin to social stress and its ability to increase anxiety and fear in response to future stress. 

"Oxytocin is usually considered a stress-reducing agent based on decades of research," said Yomayra Guzman, a doctoral student in Radulovic's lab and the study's lead author. "With this novel animal model, we showed how it enhances fear rather than reducing it and where the molecular changes are occurring in our central nervous system.'

The new research follows three recent human studies with oxytocin, all of which are beginning to offer a more complicated view of the hormone's role in emotions. All the new experiments were done in the lateral septum because it has the highest oxytocin levels in the brain and has high levels of oxytocin receptors across all species from mice to humans. 

"This is important because the variability of oxytocin receptors in different species is huge," Radulovic said. "We wanted the research to be relevant for humans, too."

Experiments with mice in the study established that 1) oxytocin is essential for strengthening the memory of negative social interactions and 2) oxytocin increases fear and anxiety in future stressful situations.

Oxtr mediates the enhancement of fear by social-defeat stress. Credit and link: doi:10.1038/nn.3465

Experiment 1: Oxytocin Strengthens Bad Memories

Three groups of mice were individually placed in cages with aggressive mice and experienced social defeat, a stressful experience for them. One group was missing its oxytocin receptors, essentially the plug by which the hormone accesses brain cells. The lack of receptors means oxytocin couldn't enter the mice's brain cells. The second group had an increased number of receptors so their brain cells were flooded with the hormone. The third control group had a normal number of receptors.

Six hours later, the mice were returned to cages with the aggressive mice. The mice that were missing their oxytocin receptors didn't appear to remember the aggressive mice and show any fear. Conversely, when mice with increased numbers of oxytocin receptors were reintroduced to the aggressive mice, they showed an intense fear reaction and avoided the aggressive mice.

Experiment 2: Oxytocin Increases Fear and Anxiety in Future Stress

Again, the three groups of mice were exposed to the stressful experience of social defeat in the cages of other more aggressive mice. This time, six hours after the social stress, the mice were put in a box in which they received a brief electric shock, which startles them but is not painful. Then 24 hours later, the mice were returned to the same box but did not receive a shock.

The mice missing their oxytocin receptors did not show any enhanced fear when they re-entered the box in which they received the shock. The second group, which had extra oxytocin receptors showed much greater fear in the box. The third control group exhibited an average fear response.

"This experiment shows that after a negative social experience the oxytocin triggers anxiety and fear in a new stressful situation," Radulovic said.

Citation: Yomayra F Guzmán, Natalie C Tronson, Vladimir Jovasevic, Keisuke Sato, Anita L Guedea, Hiroaki Mizukami, Katsuhiko Nishimori&Jelena Radulovic, 'Fear-enhancing effects of septal oxytocin receptors', Nature Neuroscience 21 July 2013 doi:10.1038/nn.3465