Molecular and behavioral mechanisms mediating paclitaxel-induced changes in affect-like behavior in mice

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.https://scholarscompass.vcu.edu/gradposters/1038/thumbnail.jp

INVESTIGATING THE ROLE OF NICOTINIC ACETYLCHOLINE RECEPTORS (nAChRs) IN THE DEVELOPMENT AND MAINTENANCE OF CHEMOTHERPY-INDUCED PERIPHERAL NEUROPATHY IN MICE

Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a major dose-limiting side effect of several anticancer drugs. The prevalence of CIPN ranges from one-third to two-thirds of cancer patients. CIPN can persist for months to years after completion of chemotherapy. Despite the efficacious use of paclitaxel in the treatment of tumors, it can induce many sensory symptoms, such as paresthesia, numbness, tingling and burning pain, and mechanical and cold allodynia, which typically are present in the hands and feet. Similar to other types of chronic pain, paclitaxel-induced CIPN is comorbid with depression and anxiety in cancer survivors, and paclitaxel induces changes in affect-like behavior in cancer-free animal models, suggesting that paclitaxel can cause long-lasting changes in mood, reducing the quality of life. While adjuvant therapies, such as duloxetine, tricyclic antidepressants, and gabapentin are prescribed to treat CIPN symptoms, none of these compounds can consistently reverse or prevent the development of CIPN. With no FDA-approved medication to treat CIPN, the purpose of the dissertation was to: i) characterize and develop a mouse model of paclitaxel-induced CIPN, ii) identify putative targets for CIPN treatment, and iii) test novel compounds for their ability to prevent and reverse CIPN in C57BL/6J mice. In the first Aim, we demonstrate that paclitaxel induces time- and dose-dependent hypersensitivity (mechanical and cold), which is potentiated by combination therapy with the chemotherapeutic carboplatin. In addition, paclitaxel-treated mice show changes in affect-like behaviors (anxiety-like, depression-like). In the second Aim, we used the prototypic nicotinic receptor (nAChR) agonist nicotine to reverse or prevent paclitaxel-induced mechanical hypersensitivity and degeneration of Intra-Epidermal Nerve Fibers (IENFs). Further, we discovered that nicotine’s antinociceptive effects in this mouse model of CIPN are mediated by the nicotinic receptor subtype α7. The third Aim used genetic and pharmacological approaches to dissect the role of α7 on the development and maintenance of paclitaxel-induced CIPN. Null mutant α7 mice (KO) hastens the onset, increases the magnitude, and delays the recovery of paclitaxel-induced mechanical hypersensitivity, as compared to littermate wildtype controls, whereas the selective α7 silent agonist R-47 to reverses and prevents paclitaxel-induced CIPN in C57BL/6J mice. We also examined the impact of R-47 on the paclitaxel-induced reduction of intraepidermal nerve fiber (IENF), as well as microglial morphology in the dorsal horn of the spinal cord. The data show that R-47 prevents paclitaxel-induced changes in microglial morphology and mechanical hypersensitivity behavior, without producing tolerance upon repeated administration. Finally, R-47 induces preference using the conditioned place test in paclitaxel-treated mice but vehicle-treated animals, suggesting that R-47 is a viable candidate for ongoing, spontaneous pain, with limited risk of abuse potential. Overall, these results support that the α7 nAChR subtype is an important target for the treatment and prevention of CIPN

Potentiation of (α4)2(β2)3, but not (α4)3(β2)2, nicotinic acetylcholine receptors reduces nicotine self-administration and withdrawal symptoms

The low sensitivity (α4)3(β2)2 (LS) and high sensitivity (α4)2(β2)3 (HS) nAChR isoforms may contribute to a variety of brain functions, pathophysiological processes, and pharmacological effects associated with nicotine use. In this study, we examined the contributions of the LS and HS α4β2 nAChR isoforms in nicotine self-administration, withdrawal symptoms, antinociceptive and hypothermic effects. We utilized two nAChR positive allosteric modulators (PAMs): desformylflustrabromine (dFBr), a PAM of both the LS and HS α4β2 nAChRs, and CMPI, a PAM selective for the LS nAChR. We found that dFBr, but not CMPI, decreased intravenous nicotine self-administration in male mice in a dose-dependent manner. Unlike dFBr, which fully reverses somatic and affective symptoms of nicotine withdrawal, CMPI at doses up to 15 mg/kg in male mice only partially reduced nicotine withdrawal-induced somatic signs, anxiety-like behavior and sucrose preference, but had no effects on nicotine withdrawal-induced hyperalgesia. These results indicate that potentiation of HS α4β2 nAChRs is necessary to modulate nicotine's reinforcing properties that underlie nicotine intake and to reverse nicotine withdrawal symptoms that influence nicotine abstinence. In contrast, both dFBr and CMPI enhanced nicotine's hypothermic effect and reduced nicotine's antinociceptive effects in male mice. Therefore, these results indicate a more prevalent role of HS α4β2 nAChR isoforms in mediating various behavioral effects associated with nicotine, whereas the LS α4β2 nAChR isoform has a limited role in mediating body temperature and nociceptive responses. These findings will facilitate the development of more selective, efficacious, and safe nAChR-based therapeutics for nicotine addiction treatment