Shining light on the dark side of oxytocin

Almost everyone’s heard of oxytocin these days. Dubbed “the love/trust hormone” by pop neurosci, oxytocin is to “love” as dopamine is to “reward” – some truth, but WAY too oversimplified! Where to start? In the sack, oxytocin is involved in ejaculation latency, the big O and pair bonding. Out on the streets (or in labs), it helps people recognize facial expressions and recall others’ faces. It may enhance trust among strangers. It may be the key to monogamy, at least in prairie voles. It reduces anxiety and stress, and promotes social interactions. It may even tweak something as abstract as morality.

Oxytocin's functions are as complicated as its structure. Source: wiki

“So what if it’s not the love drug?” you might ask. Oxytocin still sounds like the most “amazing molecule in the world.” The problem is, individual people respond to oxytocin very differently. In one study, when socially anxious people were given oxytocin through inhalers, they remembered their moms as less caring and more distant. In another study in people with borderline personality disorder, oxytocin hindered trust and cooperation. Oxytocin also seems to ENHANCE – not mitigate as previously thought – fear and anxiety levels in people who’ve suffered through traumatic events. In these individuals, it even promoted stronger recall of bad memories.

Calling oxytocin the “love drug” is not only inaccurate, but also dangerous. Not recognizing this dark side of oxytocin exploits the vulnerable – those suffering from post-traumatic stress disorder, autism, depression or social anxiety disorder, who think that an internet-bought nasal spray will help them ease their illness. Understanding how oxytocin regulates fear and anxiety is especially important, as the hormone is currently being researched as a potential anti-anxiety drug.

We know a lot about what oxytocin does. We just don’t know how it’s doing it. Oxytocin is released by the hypothalamus, situated at the base of the brain. As a hormone, it circulates and acts throughout the body and the brain. Could it be that oxytocin is acting at different sites in the brain to produce diverse actions? Under what conditions will it promote fear and anxiety? How is it enhancing fear recall?

YF Guzmán et al. (2013) Fear-enhancing effects of septal oxytocin receptors. Nature Neuroscience, doi:10.1038/nn.3465

The authors of this paper tackled these questions head on with two strains of genetically modified* mice: one lacking, and one having more of the oxytocin receptor in an area of the brain called the lateral septal (LS). Just like small molecule neurotransmitters (think dopamine, serotonin etc), oxytocin needs to bind to its receptor to have an effect; manipulating receptor levels in essence eliminates or boosts oxytocin signalling. The researchers chose the LS to study as it contains large amounts of the oxytocin receptor (so under normal circumstances oxytocin is probably doing something there), and because it’s heavily involved in stress and fear. (* For those wanting the nitty-gritty, overexpression and knockdown was achieved through local viral injection of the appropriate vectors, not whole-animal knockdown)

Researchers first tested if oxytocin is directly involved in fear in non-stressed mice. They took the two mutants and normal mice and put them in a distinctive box. They then zapped the mice with a small shock. Mice like electrical shocks as much as you – they’ll quickly associate the box with the shock, and freeze in fear when they’re put back into the box a day later. The idea is, if oxytocin signalling in the LS is involved in enhancing fear, then having more oxytocin receptors should increase freezing.

Which didn’t happen! As you can see, neither increasing (dark blue bar) nor decreasing (light blue bar) oxytocin receptors had an effect on freezing, compared to the controls (white bar). This suggests that in normal, unstressed individuals, oxytocin in the LS does NOT directly regulate fear and anxiety. Could it be that oxytocin plays a more modulatory role in fear then? As in, it will only promote fear when an individual is already stressed?

To test this hypothesis, researchers first needed to stress out the mice. While you can do it with robots, researchers settled on a more socially relevant method: social defeat. They put a large, aggressive bully into the mice’s habitat, and let the him intimidate the mice for 6 hours. Previous results tell us that social defeat increases oxytocin release in the LS, and if extended for long periods, can induce symptoms like depression and social withdrawal in the bullied. After a tortuous 6 hours, researchers removed the mice and once again, shocked them in a box and tested them for freezing a day later.

As you can see in the left graph, social defeat dramatically increased freezing in normal mice (first two bars, WT/wild-type, orange compared to grey), but this was completely abolished by wiping out oxytocin receptors (last two bars, green bar compared to grey). On the other hand (right graph), in mice subjected to social defeat, mice that have more oxytocin receptors (dark blue bar) froze much more than normal mice (orange bar). These results tell us that oxytocin enhances fear in stressed individuals, but doesn’t affect normal mice.

So what's going on? Is oxytocin enhancing the EXPERIENCE of social defeat, in which the mice perceive a small aggressor as a more intimidating one? Researchers noticed that all bullied mice, regardless of oxytocin receptor levels, behaved similarly – those having more oxytocin receptors did not cower more than normal. Perhaps oxytocin is not changing the social interaction per se, but enhancing the bad memory of being tormented?

To test this, researchers put the defeated mice back together with the bully. While normal mice tentatively approached the bully several times, mice with more oxytocin receptors kept their distance. Mice without oxytocin receptors seemed to have forgotten the episode and hanged around the bully way more than normal mice. So it does seem that increased oxytocin signalling enhances bad memories, and predisposes a traumatized individual to more fear and anxiety when subjected to further stress later on.

Researchers then tried to figure out how oxytocin strengthens a bad memory, and identified a protein called ERK1/2 as a main signalling messenger. When they inhibited ERK1/2 with a drug called U0126 (black bar on the far right), the effects of social defeat on enhancing bad memories (orange bar) were eliminated. The drug did not affect fear memory in non-stressed (NS) mice (grey and black bars on the left). Interestingly, oxytocin activates alternatively signalling proteins in other brain regions such as the central amygdala, which DECREASES anxiety. So it seems that oxytocin is “two-faced”, and depending on which brain area it’s activating on, can enhance both “love” and fear.

In mice stressed out from social defeat (SD), inhibiting the messenger ERK1/2 with U0126 erased oxytocin's enhancing effect on bad memories. NS: no social defeat.

As mentioned before, oxytocin circulates throughout the body and the brain. It would be interesting to see how systemic oxytocin influences fear memory. Could it be that stress differentially alters oxytocin receptor levels in different areas of the brain, changing the balance between promoting and eliminating fear? Does oxytocin have the same effect on different types of stress? Does oxytocin signalling in the LS go awry in people with anxiety disorders? Perhaps giving nasal oxytocin is not the best anti-anxiety med, and targeting its downstream signalling pathways in fear-inducing brain areas (like the LS) might be a better approach?

Finally, what is the role of oxytocin in influencing individual behaviour in social interaction? This study clearly tells us that oxytocin does not unidirectionally decrease anxiety. Maybe, as the authors suggested, it is a signal that focuses our attention to different social contexts and cues, making them more noteworthy and our experiences more long lasting. We don't yet know. Hopefully, more research will continue to reveal the multiple faces of this complicated and fascinating molecule.

Guzmán YF, Tronson NC, Jovasevic V, Sato K, Guedea AL, Mizukami H, Nishimori K, & Radulovic J (2013). Fear-enhancing effects of septal oxytocin receptors. Nature neuroscience PMID: 23872596

Note: For those interested in learning more about oxytocin, @Scicurious has an awesome blog series going on. Check it out!

Edit: Thanks to Samuel for pointing out in the comments that oxytocin is also considered a neurotransmitter.