Measuring Depression After Chemotherapy [online video]
Original Publication Date
Delayed Deficit in Operant Responding for Palatable Food in Sated Male Mice with Chemotherapy-Induced Peripheral Neuropathy (Measuring Depression after Chemotherapy) --Julie A. Meade. Mentor: Dr. M. Imad Damaj.
Half a million patients a year with breast cancer, ovarian cancer, or non-small cell lung cancer will receive the antineoplastic paclitaxel. While there are approved treatments for select paclitaxel-related side effects, such as nausea, efficacious treatments for cognitive, pain, and emotion-related side effects are lacking. For example, patients receiving paclitaxel report higher incidences and longer duration of treatment-resistant depression than patients receiving other classes of chemotherapeutics. To characterize the nuances of paclitaxel-induced depression-like behavior in a mouse model, C57BL/6J adult mice in a food-restricted state were trained to perform an operant responding task that required 10 nose-poke responses to earn one pellet of palatable food (FR10). Trained mice received four injections of 8mg/kg paclitaxel (32mg/kg cumulative, i.p.) or vehicle control, and mice continued FR10 testing daily for one month. Separate cohorts of male and female C57BL/6J mice were trained to perform progressive ratio (PR2) operant responding (1, 2, 4, 8…1,024) while on ad libitum chow. Subjects received eight injections of 8mg/kg paclitaxel (64mg/kg cumulative, i.p.) or vehicle control, and underwent weekly PR2 testing for three months. While 32mg/kg paclitaxel was insufficient to induce deficit in FR10 responding in food-restricted males, sated males treated with 64mg/kg paclitaxel began to show deficit in PR2 responding two weeks after cessation of injections, reaching a nadir in behavior one month after cessation of injections. Even though both sexes had mechanical hypersensitivity for the duration of the study, females never developed PR2 deficit, and males gradually recovered from PR2 deficit. These findings suggest that paclitaxel may reduce motivation-like behavior in a time-, sex-, and effort-dependent manner, independent of nociception. Future studies will investigate the relationship between neuropathy and operant responding for palatable food using pharmacological and genetic approaches, as well as the impact of different classes of chemotherapeutics on operant responding.
Supported by: Ruth L. Kirschstein National Research Service Award Individual Predoctoral Fellowship to Promote Diversity in Health-Related Research 1F31CA224930-01A1; NIH grant 1R01-CA206028-01; NIHNCI Cancer Center Support Grant P30-CA016059.
Why did I get out of bed today? What’s the point of even trying? We’ve all had days like this, where we don’t have motivation. But what if that was your life, every day? For ten-million people with major depressive disorder in the US, that is a reality. And it severely impairs their ability to do tasks of daily living. Unfortunately, for 70% of these patients, standard antidepressants do not fix their lack of motivation. Similarly, half of breast cancer survivors report moderate to severe lack of motivation that will last for 6 months after chemo treatment. This is a major problem.
Part of the reason why we don’t have a magic pill that treats everyone’s blues is because our mouse models of depression are faulty. The most common test for antidepressant activity is to see if the drug makes the mouse tread water for longer. I don’t know about you, but I don’t spend my days treading water, and I’m not looking for a pill that will make me tread water longer. I want a drug that will help patients have the motivation to go to work, to take care of themselves.
So, what I do, is I develop a new mouse model. I give this mouse the same chemotherapy that human cancer patients get. And I want to see if it impacts their motivation. To do this, I put the mice in a machine, called an operant box. And this machine has a lever. When the mouse presses the lever, he gets one piece of candy. Each next piece of candy costs double. Two lever presses, four lever presses, up to over a thousand lever presses for one measly piece of candy.
And here’s what I saw: The mice who got treated for breast cancer chemotherapy, they gave up faster. They just lacked motivation. If we gave these same mice a bowl of mouse candy, they ate it all. If we put them in a running wheel, they ran as much as the placebo mice. So this means the mice weren’t fatigued or having lack of appetite due to chemo, but that they just did not want to do the work. Now that we have this mouse model, we can use it to help develop new antidepressants for humans. Hopefully, we’ll be able to find something in the mice that increases their time treading water, and also the amount of work they’re willing to do for the candy. So that way, our patients with major depressive disorder, or treatment resistant depression from chemotherapy, will be able to go and live full, functional lives.
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