1F31CA224930-01A1 (F31) ApplID: 9610013 | |||
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Title | Molecular and behavioral mechanisms mediating paclitaxel-induced changes in affect-like behavior in mice | ||
Institution | VIRGINIA COMMONWEALTH UNIVERSITY, RICHMOND, VA | ||
Principal Investigator | MEADE, JULIA | NCI Program Director | McNeil |
Cancer Activity | Comp Min Biomed Prog | Division | CRCHD |
Funded Amount | $35,050 | Project Dates | 09/25/2018 - 09/24/2020 |
Fiscal Year | 2018 | Project Type | Grant |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Basic Behavioral and Social Science (100.0%) Behavioral and Social Science (100.0%) Cancer Survivorship (100.0%) Chemotherapy (100.0%) Depression Research (100.0%) Taxol (100.0%) |
N/A | ||
Research Type | |||
Patient Care and Survivorship Issues | |||
Abstract | |||
Abstract A common finding in longitudinal studies of cancer survivors is long-term changes in mood, such as dysphoria and emotional deficit, including anhedonia. However, there is no efficacious treatment for chemotherapy- induced depression in survivors who had received paclitaxel, an antineoplastic commonly used in the treatment of breast, pelvic, head and neck, and non-small cell lung cancers. Unfortunately, paclitaxel-induced changes in affect can persist for up to five years or longer following completion of treatment. With the Baby Boomer population approaching peak cancer age, it is dire that the mechanisms behind paclitaxel-induced changes in mood are uncovered so as to improve the quality of life of the projected 19 million cancer survivors in 2024. Therefore, in order to study paclitaxel-induced reward deficit over an extended period, cancer-free male C57BL/6J mice were treated with one cycle of four injections of vehicle or paclitaxel (32mg/kg cumulative) and periodically assessed for anhedonia-like behaviors. Paclitaxel caused significant time-dependent deficits in sucrose preference and conditioned place preference (CPP) for morphine. Kappa opioid receptors (KORs) have been reported to modulate sucrose and morphine reward in humans and rodent models, so we investigated KOR signaling as a putative mechanism of paclitaxel-induced anhedonia. The selective KOR antagonist norbinaltorphimine (norBNI) reversed paclitaxel-induced sucrose preference deficit. At the molecular level, paclitaxel-treated mice had higher relative expression of prodynorphin mRNA, which is the precursor for endogenous KOR agonists, in the nucleus accumbens (NAc), a limbic region involved in reward. Because KOR signaling in the NAc can cause anhedonia via modulation of dopamine (DA) signaling, we used the [35S]GTP?S assay to measure DA D2 receptor (D2R) function in the NAc. A history of systemic paclitaxel acutely and transiently inhibited quinelorane (D2R agonist)-stimulated binding, suggesting decreased function of the D2R. Our preliminary data suggest that paclitaxel-induced changes in affect-like behavior may be due to time- dependent dysregulation of KOR and D2R signaling in the limbic system. Future studies will employ conditioned place preference for drugs of abuse, conditioned place aversion for KOR agonists, and operant responding for food rewards to further characterize paclitaxel-induced changes in affect-like behavior. In order to demonstrate a role of the KOR neuronal system in these behavioral changes, norBNI will be used in experiments that aim to prevent or reverse these behaviors, as well as to prevent or reverse changes in neurochemistry. Male and Female mice will be included in these studies." |