DOI
https://doi.org/10.25772/HZR5-6328
Author ORCID Identifier
0000-0002-1639-3756
Defense Date
2020
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmacology & Toxicology
First Advisor
Dr. M. Imad Damaj
Second Advisor
Dr. Dana E. Selley
Abstract
Paclitaxel and oxaliplatin are two chemotherapeutics that cause acute neurotoxicity and chemotherapy-induce peripheral neuropathy (CIPN) in 70-90% of cancer patients. Chemotherapy-induced sensory changes are correlated with depression and anxiety. We characterized the effects of these drugs on sensation and various mood-related behaviors in mice, to determine if changes in sensation are associated with depression-like behavior, to explore putative mechanisms of chemotherapy-induced depression-like behavior (Aim 1), and to develop a mouse model of chemotherapy-induced operant responding deficit (Aim 2). In Aim 1, we observed that a cumulative dose of 32 mg/kg paclitaxel induced mechanical hypersensitivity and transiently reduced preference for sucrose solution. Paclitaxel-induced deficits in sucrose preference were kappa opioid receptor (KOR) mediated, whereas mechanical hypersensitivity was not. Further, paclitaxel pretreatment increased expression of precursor peptide agonists for KOR, and we also observed modulation of ligand-stimulated guanine nucleotide exchange in KOR. The findings of Aim 1 suggest that dysregulation of the KOR system underlies the initial aversiveness of paclitaxel in male C57BL/6J mice, but not necessarily sensory changes. In Aim 2, we focused on operant responding deficit, as a measurement of impairment of tasks of daily living. To characterize the contributions of chemotherapy-induced sensory changes on operant responding in a mouse model, two inbred mouse strains (C57BL/6J and Balb/cJ) trained to perform an operant task for palatable food received infusions of either vehicle, paclitaxel (32 mg/kg or 64 mg/kg, cumulative), or oxaliplatin (30mg/kg, cumulative). All chemotherapeutic agents induced profound mechanical hypersensitivity for the duration of the study; however, only 64 mg/kg paclitaxel (administered on Day 0, 2, 4, 6, 10, 12, 14, and 16) in male C57BL/6J mice was able to reduce operant task performance, with behavioral deficits emerging at the 6 Weeks time point, and spontaneously resolving by the 10 Weeks time point. The findings of Aim 2 suggest chemotherapeutic-, dose-, sex-, strain-, and time-dependent effects on operant responding. This deficit in operant responding was not KOR mediated. The results of these two aims suggest that chemotherapy-induced mechanical hypersensitivity is not sufficient to induce and/or maintain changes in depression-like behaviors, and that the mechanisms that mediate depression-like behaviors upon initial administration of chemotherapy are distinct from the mechanisms that mediate depression-like behaviors after prolonged abstinence from chemotherapy. Characterization of the molecular and behavioral mechanisms of chemotherapy-induced changes in affect-like behavior in mice can lead to the development of therapeutic interventions for cancer survivors with treatment-resistant depression.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
4-30-2020
Included in
Animals Commons, Behavior and Behavior Mechanisms Commons, Disease Modeling Commons, Investigative Techniques Commons, Pathological Conditions, Signs and Symptoms Commons, Pharmaceutical Preparations Commons
Comments
This dissertation shows that chemotherapy causes pain-like and depression-like behaviors in mice. Ongoing pain state is not sufficient to cause depression. Different chemotherapeutic families cause different behavioral outcomes in mice.