Tumors can cause classic symptoms of depression in rats, according to a new study published online in PNAS this week.

Image: Understanding Animal Research

"What's really cool about this paper is that it shows without a doubt that there are depressive-like behaviors induced in these rats before these rats become [sick]," said Keith Kelley, an immunophysiologist at the University of Illinois at Urbana-Champaign, who was not involved in the research.

Researchers have long known that individuals suffering from chronic illness are at a greater risk of depression, but whether it was a direct cause of the illness or a psychological reaction to being sick was unclear. "By using this animal model of cancer we were able to isolate just the physiological effects of the tumors from the psychological effects that you get in human studies," said Leah Pyter, a behavioral neuroscientist at the University of Chicago, who led the study. "The tumors themselves are sufficient to induce depression."

Pyter and her colleagues induced mammary tumors in rats using a chemical carcinogen known as N-nitroso-N-methylurea (NMU). In a forced swimming test, the rats with chemically induced tumors spent more time floating instead of swimming compared with healthy controls, a classic sign of depression. And while healthy rats prefer weak sugar water to tap water, the rats with tumors showed no such preference.

The rats exhibited these depressive-like behaviors well before they showed any overt signs of illness from the tumors themselves. They showed no difference in eating habits or social behavior, and they did not lose weight, like rats with an induced acute infection often do.

This study "supports what we've been saying for years: that sickness can be dissociated from mood changes," Kelley said.

The rats with tumors showed a boost in levels of cytokines known to mediate behavioral changes after bacterial infection or brain trauma, both in the plasma and in the hippocampus, a brain region associated with depression. This supports the notion that these cytokines regulate the behavioral changes the researchers saw, though how exactly the cytokines elicit this effect is not yet clear.

To make matters worse, Pyter said, her findings suggest that the cytokine levels may be further misregulated because of the cancer's effect on the stress response pathway. Rats with tumors had a reduced increase in the stress response hormone corticosterone after exposure to a stressor. "Ordinarily glucocorticoids suppress cytokines," Pyter said. Low levels of glucocorticoids could hinder this suppression, which "could exacerbate the effects of cytokines on the brain and behavior."

The next step is to start to figure out the mechanism by which the cytokines trigger these behavioral changes, Pyter said. Also, she noted, many chemotherapies are cytokine-based, and the findings may help doctors decide when those therapies would be appropriate for cancer patients.


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