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Chemotherapy Rats as a Tool to Study Treatment-Resistant Depression in Cancer Survivors

March 05, 2020
By Julie Meade, Ph.D. Candidate in the Department of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, MCV Campus, Richmond, Virginia

The impending silver tsunami of Baby Boomers approaching peak cancer age presents a unique challenge, though not necessarily when it comes to cancer treatments, which have drastically improved in the last decade.  The problem lies within the debilitating side effects of these efficacious therapies: pain and depression.  For example, paclitaxel is a common chemotherapy medication used for breast cancer (among other cancers) that cures half a million cancer patients a year.  However, paclitaxel is associated with pain and treatment-resistant depression that can last for years after finishing chemo.  Even though these side effects commonly occur together after paclitaxel treatment, recent experiments performed by the Negus Lab at Virginia Commonwealth University suggest that treating pain doesn’t necessarily fix the lack of motivation associated with depression, and that both are likely two independent consequences of paclitaxel treatment.

With a projected 20 million cancer survivors by the end of the next decade, there is a pressing need to find better antidepressants for patients who develop depression after chemotherapy.  Testing experimental antidepressants typically entails giving them to rodents in a depressed-like state.  These rodents show simple signs of depression when treated with chemotherapy, such as hiding, loss of interest in tasty foods, and giving up at trying to escape. But lack of motivation is harder to detect in rodents.  Thats part of the reason why currently available antidepressants fail to treat this symptom in cancer survivors; in clinical trials of drugs that have been tested in lab animals, antidepressants for patients with a history of paclitaxel treatment are about as effective as sugar pills.

Pain signs are easier to detect in rodents.  The Negus Lab gave healthy rats a variety of cancer fighting drugs, including paclitaxel, followed by gentle poking on their paws with a tool that resembles a toothbrush, but with just one bristle.  Rats that were treated with higher doses of chemo were the most sensitive to light touch, shaking their paws or jumping when lightly poked.  This suggests that the chemo rats were experiencing pain with light touch, just like the human cancer survivors with allodynia, who perceive light touch as painful.

The tricky part was finding a behavior that looks like lack of motivation in the rats.  Cancer survivors with neuropathy (nerve damage) can experience side effects like stabbing, tingling pain in their fingers. This pain can make cancer survivors with neuropathy struggle to do something as simple as typing on a keyboard, causing them to feel overwhelmed and down.  The scientists hypothesized that rats treated with chemo would act like depressed human cancer survivors and refrain from doing a task that could cause them more pain: pressing a lever for food.  All four chemo drugs temporarily decreased the rats lever pressing, indicating that the treatment reduced the motivation of the rats to do a specific task to get fed.

There is a high correlation between pain and depression in cancer survivors. This led the scientists to hypothesize that fixing pain could fix lack of motivation. Hence, they tested if blocking paclitaxel-induced pain would increase motivation.  The strong analgesic morphine prevented paclitaxel rats from shaking their paw or jumping when lightly poked, blocking the pain response; however, these paclitaxel rats did not increase their lever pressing for food. Disappointingly, pain relief was not sufficient to motivate the rats to work harder to earn more food.  These observations help illustrate why treating pain in cancer survivors is not sufficient to treat their depression. 

While training an animal to lever press for food is not a new method, these lever pressing chemo rats are a better representation of lack of motivation than the standard rodent depression tests.  Using these lever pressing chemo rats in future experiments, scientists will finally be able to test new antidepressants specifically for their effects on motivation.  Experimental antidepressants that improve standard rodent depression tests and increase lever pressing would have a higher chance of success in cancer survivors.  For an ever-increasing population of cancer survivors and other individuals with treatment-resistant depression, this method has the potential to impact the quality of life of millions of patients who continue to struggle with lack of motivation despite trying antidepressants.

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