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Of mice, and men who stress them out: How scientists’ sex can affect lab mice’s reaction to drugs

Not only do mice prefer women to men, sex of the researcher affects their response to antidepressant ketamine, finds University of Maryland study published in Nature Neuroscience.

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Bengaluru: Laboratory mice are more comfortable being handled by women than by men; this is something the scientific community has known through anecdotal evidence for a while.

Now, this aversion of mice to men has, almost by accident, helped researchers better understand why some people don’t respond well to the anti-depressant ketamine, while others do.

In a study published in the journal Nature Neuroscience last month, University of Maryland researchers showed that mice responded better to the anti-depressant effects of ketamine when the drug was administered by men.

This, ironically, was because the mice’s stress response in a particular area of the brain, the hippocampus, had been heightened due to being handled by the men.

This has implications on how people respond to the drug too, albeit not in terms of whether a man or woman administers it.

“Our findings in mice suggests that activating a specific stress circuit in the brain may be a way to improve ketamine treatment,” said Dr Todd Gould, one of the authors and a professor of psychiatry at the University of Maryland School of Medicine, in a press release about the study.

The idea is that ketamine might have a better antidepressant effect if it is combined with “activation of this brain region” by either another drug or some kind of “specific stressor”, he added.

Also read: Now, ‘party drug’ ketamine will work as a quick antidepressant? US researchers tell us how

Smell, stress, and a surprising result

The University of Maryland (UoM) researchers arrived at their findings after noticing that ketamine’s anti-depressant effects didn’t work when administered by the majority of the researchers, who were women, but did when the few male researchers handled the animals.

During early experiments, the team found that results with mice could be skewed depending on the biological sex of the experimenter who was handling the animals. The mice seemed to respond better to women and seemed less stressed, but the ketamine response was evoked only by men. The team checked with other labs studying mouse responses to ketamine, and they reported similar issues too.

A randomised, blinded study showed that lab mice were also more stressed by and averse to the scent of male experimenters and were more relaxed around the smell of female humans present in T-shirts, as well as cotton swabs rubbed on the wrists or elbow or behind the ear. When the researchers blocked the ability to smell in mice, they showed no preference for objects with female scents.

Some previous studies have also shown that laboratory mice seem to prefer not just being handled by females but also their smell. In a 2014 study, for instance, when mice were exposed to T-shirts worn by male and female humans, they preferred being around clothes worn by women. On the other hand, the smell of men caused a “stress response”.

In the case of the UoM researchers, they noticed another peculiar thing in their work with anti-depressants and mice — that the drug desipramine worked no matter who was handling the mice, but ketamine seemed to work only when male researchers administered it.

To understand why, they looked at a hormone called corticotropin-releasing factor (CRF). It is located in the hippocampus, the part of the brain responsible for learning and memory, and is associated with depression. They found that this human-male-scent-induced aversion and stress susceptibility was mediated by the activation of CRF, which triggered the stress response circuit.

Corticotropin is responsible for producing stress responses like heightened anxiety and suppression of appetite.

When female researchers administered ketamine, the mice did not respond. However, when they paired it with CRF, the mice showed a reduction in depression through ketamine.

The team concluded that it is the activation of the CRF stress response circuitry that enables ketamine to function as an anti-depressant.

The study has thrown some light on non-responsiveness to ketamine as an antidepressant.

The researchers believe that people may have higher or lower levels of CRF and this affects the efficacy of ketamine, although the findings cannot be translated directly to humans and will need to be tested, evaluated, and replicated first.

Ketamine and depression

Ketamine is best known as a tranquiliser for animals and an illegal recreational drug for humans, but it has also been gaining increasing attention for its anti-depressant properties. It’s oftentimes more effective and works faster than conventional anti-depressants — within hours rather than weeks.

An earlier study on mice had found that ketamine treatment activated neurons in the hippocampus — the same region of the brain associated primarily with memory and learning, and where the hormone CRF is produced. While traditional antidepressants promote the growth of new cells in the hippocampus, ketamine lights up existing pathways in the brain.

However, some people (and mice) with depressive disorder have been shown to be resistant to ketamine. The molecular and pharmacological mechanisms behind this have been unclear so far.

Of mice and men

​When around men, mice seem to experience a stress response that’s equivalent to being restrained in a tube for 15 minutes.

This is because men release many more pheromones, or airborne hormones, than women do. These scents typically alert rodents to the presence of other male animals nearby, causing a spike in stress. This stress response can produce analgesia or reduced sensitivity to pain (in the face of high stress or danger), and this can influence lab results.

While the response of mice to the sex of researchers has clear implications for general laboratory study results, the mechanisms behind this are not yet quantified.

What is of some consolation to researchers is that mice that get stressed out around men also get acclimatised to male presence over time. In addition, the presence of female smells may counteract the effects of male scents.

And it’s not just the sex of researchers that can potentially impact results — studies have shown that mice are also affected by other stressors such as the condition of their cages and their environment, their diets and sleep cycle, etc.

(Edited by Asavari Singh)

Also read: Donkeys were domesticated just once in history, study finds. They went on to change civilisation


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