Date of Degree
PhD (Doctor of Philosophy)
Susan K. Lutgendorf
Alan Kim Johnson
Considerable data demonstrate a high prevalence of depression symptoms in patients with cancer, with some studies showing the prevalence for major depressive disorder (MDD) to be as high as 50%. Because depression researchers have found that a significant relationship exists between depression symptoms and indices of systemic inflammation and because several cancer types exploit the mechanisms of the body's inflammatory response to aid in their own progression, it was hypothesized that tumor in the body could be a cause of depression symptoms in cancer patients. Examination of this question was conducted using an immunocompetent mouse model of ovarian cancer and several measures of depressive-like and sickness behavior. Initial investigation of the model (Chapter 2) involved a series of pilot experiments that addressed methodology and demonstrated that ID8 murine ovarian carcinoma was capable of inducing elevated levels of systemic IL-6 and depressive-like behavior, specifically anhedonia as measured by a decrease in sucrose solution. In Chapter 3, a larger experiment (Experiment 1) was conducted that examined the effect of ovarian tumor on sucrose intake, food intake, body weight, locomotion, and rotarod performance. Results in the study indicated that sucrose-measured anhedonia in the model was not confounded by anorexia because tumor-bearing mice and control mice exhibited no significant difference in appetite. In Chapter 4, a second experimental factor, social housing, was added alongside tumor condition, and a second measure of depressive-like behavior, tail suspension test (TST) immobility, was added to measures from the previous experiment. The results of this second large experiment (Experiment 2) demonstrated that ovarian tumor had no significant effect on TST immobility, even though it did cause mice to exhibit less motor activity in the home cage. Housing condition did affect TST immobility. Mice that were individually-housed exhibited significantly more TST immobility than group-housed mice. Also, individually-housed mice exhibited less sucrose intake than group-housed mice. This gave rise to a significant interaction in sucrose preference among the four experimental groups where individually-housed tumor-bearing mice showed less sucrose preference than the other groups. In Chapter 5, systemic proinflammatory and antiinflammatory cytokines from both Experiment 1 and Experiment 2 were examined. Results indicated that both proinflammatory and antiinflammatory cytokines were significantly higher in tumor-bearing mice than in control mice, and these effects were largest for interleukin-6 (IL-6) and IL-10. Among tumor-bearing mice, significant correlations between IL-1β, IL-6, tumor necrosis factor alpha (TNF-α), transforming growth factor beta (TGF- β) and locomotion were noted, but there was no significant correlation between cytokines and anhedonia. No significant effect of housing condition on cytokines was found. In Chapter 6, principal findings of the project are summarized and discussed with a focus on anhedonia and psychomotor slowing in MDD. Current evidence suggests that dopaminergic and glutamatergic systems in the brain may underlie anhedonic and psychomotor features in inflammation-induced depression. Thus, future investigation of the mediators between ovarian tumor and these depressive-like behaviors in the model may benefit from targeting these specific neural mechanisms.
Copyright 2010 Donald Michael Lamkin