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The antineoplastic paclitaxel is associated with negative affective outcomes, such as depression, anxiety, and decreased quality of life during treatment and convalescence. With the Baby Boomer population approaching peak cancer age, it is dire that the mechanisms behind paclitaxel-induced changes in mood are uncovered. Cancer-free male and female C57BL/6J mice were treated with one set of four injections of vehicle or paclitaxel (32mg/kg cumulative), or two sets of four injections of vehicle or paclitaxel (64mg/kg cumulative), and periodically assessed for depression-like behaviors. Paclitaxel caused significant, time-dependent deficits in sucrose preference and operant responding for palatable food. Because there is growing evidence to support the role of kappa opioid receptors (KORs) in stress-mediated depression and reward dysfunction, we investigated KOR signaling as a putative mechanism of paclitaxel-induced depression-like behaviors. The selective KOR antagonist norbinaltorphimine (norBNI) reversed paclitaxel-induced attenuation of sucrose preference. At the molecular level, paclitaxel time-dependently induced an increase in the expression of Prodynorphin mRNA, the precursor for endogenous KOR agonists, in the nucleus accumbens (NAc). Using the [35S]GTPγS assay, we discovered that a history of paclitaxel time-dependently attenuated activation of dopamine D2 receptors (D2R) and KORs in the NAc but not caudate putamen. These data suggest that paclitaxel-induced changes in affect-like behavior may be due to time- and region-dependent dysregulation of KOR and D2R signaling. These observations help to establish the roles of KOR and D2R systems in paclitaxel-induced disruption of behavioral reward, thus revealing potential neurochemical targets for therapeutic intervention in cancer survivors with treatment-resistant depression.
paclitaxel, chemotherapy induced peripheral neuropathy, nucleus accumbens, depression, reward, motivation, anhedonia, mice, kappa opioid receptors, dynorphin, dopamine, dopamine D2 receptors
M. Imad Damaj
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VCU Graduate Research Posters