title: Fluoxetine prevents the development of depressive-like behavior in a mouse model of cancer related fatigue.
abstract: Cancer patients frequently suffer from fatigue, a complex syndrome associated with tiredness and depressed mood. Cancer-related fatigue (CRF) can be present at the time of diagnosis, escalates during treatment, and can persist for years after treatment. CRF negatively influences quality of life, limits functional independence, and is associated with decreased survival in patients with incurable disease. We have previously shown that increased pro-inflammatory cytokine expression in the brain contributes to depressive- and fatigue-like behaviors in a mouse model of CRF. Inflammatory cytokines increase the activity of indoleamine 2,3-dioxygenase (IDO) and kynurenine 3-monooxygenase (KMO), which competitively reduce serotonin synthesis. Reduced serotonin availability in the brain and increased production of alternative neuroactive metabolites of tryptophan are thought to contribute to the development of depression and fatigue. The purpose of this study was to determine the effects of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), on brain cytokines and behavioral measures of fatigue and depression in tumor-bearing mice. Here we show that tumor growth increased brain expression of pro-inflammatory cytokines and KMO. Treatment with fluoxetine had no effect on tumor growth, muscle wasting, fatigue behavior, or cytokine expression in the brain. Fluoxetine, however, reduced depressive-like behaviors in tumor bearing mice. In conclusion, our data confirm that increased brain expression of pro-inflammatory cytokines is associated with tumor-induced fatigue- and depressive-like behaviors. However, it is possible to separate the effects of tumor growth on mood and fatigue-like behaviors using SSRIs such as fluoxetine.
authors.affiliation: Department of Neuroscience, The Ohio State University, 333 W. 10th Ave., Columbus, OH, United States.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Norden
authors.affiliation: Department of Physiology and Cell Biology, 370 W. 9th Ave., The Ohio State University, Columbus, OH, United States.
authors.forename: Raymond
authors.initials: R
authors.lastname: Devine
authors.affiliation: Division of Biosciences, College of Dentistry, The Ohio State University, 305 W. 12th Ave., Columbus, OH, United States.
authors.forename: Sabahattin
authors.initials: S
authors.lastname: Bicer
authors.affiliation: College of Nursing, The Ohio State University, 1585 Neil Ave., Columbus, OH, United States.
authors.forename: Runfeng
authors.initials: R
authors.lastname: Jing
authors.affiliation: Division of Biosciences, College of Dentistry, The Ohio State University, 305 W. 12th Ave., Columbus, OH, United States.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Reiser
authors.affiliation: Department of Physiology and Cell Biology, 370 W. 9th Ave., The Ohio State University, Columbus, OH, United States; College of Nursing, The Ohio State University, 1585 Neil Ave., Columbus, OH, United States.
authors.forename: Loren E
authors.initials: LE
authors.lastname: Wold
authors.affiliation: Department of Neuroscience, The Ohio State University, 333 W. 10th Ave., Columbus, OH, United States; Institute for Behavioral Medicine Research, The Ohio State University, 460 Medical Center Dr. Columbus, OH, United States.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Godbout
authors.affiliation: College of Nursing, Marquette University Milwaukee, WI, United States. Electronic address: donnalee.mccarthy@mu.edu.
authors.forename: Donna O
authors.initials: DO
authors.lastname: McCarthy
mesh_terms: D000230:Adenocarcinoma / Q000150:complications; D000284:Administration, Oral; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003110:Colonic Neoplasms / Q000150:complications; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003863:Depression / Q000209:etiology* / Q000517:prevention & control*; D004195:Disease Models, Animal; D005221:Fatigue / Q000150:complications* / Q000188:drug therapy* / Q000209:etiology; D005260:Female; D005473:Fluoxetine / Q000008:administration & dosage*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008124:Locomotion / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009043:Motor Activity / Q000187:drug effects; D012333:RNA, Messenger; D018709:Statistics, Nonparametric; D013997:Time Factors
chemical_list: D018687:Antidepressive Agents, Second-Generation; D016207:Cytokines; D012333:RNA, Messenger; D005473:Fluoxetine
keywords: Cancer; Depression; Fatigue; Fluoxetine; Neuroinflammation; Serotonin