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

IMPACT OF CHEMOTHERAPY ON NICOTINE DEPENDENCE

Although cigarette smoke has been implicated in a causal relationship with various types of cancers, around 62% of all cancer patients are current smokers, recent quitters, or former smokers. While most patients who are smokers are motivated to quit after cancer diagnosis, 25 -30% of these patients continue to smoke. Furthermore, most quitters relapse after 2-3 years of post-chemotherapy. This represents a major health concern since several clinical studies revealed that perpetuation of smoking in cancer populations attenuates patient\u27s well-being and quality of life. Smoking may impair healing, attenuate the efficacy of chemotherapy, increase the disease complications and diminish survival rates. However, the factors that involved in nicotine dependence in cancer patients are poorly understood. xii According to human research, it was suggested that tumor site, impact of cancer therapy and disease prognosis could be responsible of continuation of tobacco smoking among cancer patients and survivors. Recently, chemotherapy was shown to cause emotional deficits in humans (anxiety, insomnia and depression) and animals. In this project, we focused on the chemotherapeutic agent, paclitaxel, because it is widely used to treat solid tumors such as lung, head, neck and breast cancer. We previously reported that paclitaxel induced general affective deficits in mice such as anhedonia, anxiety and depression-like behaviors. We therefore hypothesized that the chemotherapeutic agent, paclitaxel may alter the rewarding and withdrawal properties of nicotine. We investigated the impact of paclitaxel on spontaneous nicotine withdrawal and nicotine reward in C57BL/6J mice by using variety of behavioral tests. Our findings showed that paclitaxel worsened the somatic and affective signs of nicotine withdrawal in male mice as well as attenuated of nicotine reward in the CPP assay. These behavioral changes were not due to an impact of nicotine metabolism by paclitaxel. Overall, paclitaxel changed the behaviors during nicotine withdrawal and reward and that suggested changing in the smoking behavior after exposure to chemotherapy

Exploring the discriminative stimulus effects of e-cigarette aerosols in rodents

Tobacco cigarette smoking has been decreasing in the US and is being replaced by electronic cigarettes (e-cig) also referred to as electronic nicotine delivery systems (ENDS). ENDS are battery-powered devices that heat and aerosolize a liquid mixture constituting of a vehicle, drug, and flavorings. ENDS are often promoted as a smoking cessation aid. Unfortunately, e-cigarettes have become very popular among youth including many who have never used combustible cigarettes. Only a small percentage of teens used e- cigarettes in 2011 but by 2019 use peaked with 28% of high school students and 11% of middle school students reporting e-cigarette use decreased somewhat in 2020 but remains a health issue affecting children, and youth. The rapid increase and high prevalence of e-cigarettes use highlights the importance of developing a scientific, data-driven approach to understanding their potential health implications. Animal models of e-cigarette exposure with pharmacokinetics and vaping parameters resembling human e-cigarette users will be important to scientists, clinicians, and regulators, have not to be adequately developed. The overarching goal of the project was to explore the abuse-related subjective stimulus effects of nicotine aerosol using the drug discrimination procedure in rodents. First, the nature of inhaled nicotine was compared to injected nicotine and the impact of puffing parameters and device power on the DS of inhaled nicotine was assessed. Second, the pharmacological basis underlying nicotine aerosol’s discriminative stimulus was examined. Third, exteroceptive and interoceptive components of the discriminative stimulus of inhaled nicotine was explored. Lastly, the impact of menthol on the discriminative stimulus effect of nicotine aerosol was measured. Inhaled nicotine aerosol produced CNS-mediated discriminative stimulus effects equivalent to those of injected nicotine. Number of puffs and wattage played a role in the stimulus effects of inhaled nicotine, but other variables such as vehicle composition, nicotine forms were not involved. The discriminative stimulus effects of inhaled nicotine were mediated by nicotinic acetylcholine receptors similar to the stimulus of injected nicotine. Menthol enhanced the abuse-related effects of nicotine aerosol, which could provide support for the hypothesis that eliminating menthol from both e-liquids and combustible cigarettes may reduce their abuse liability. Addition of tobacco flavors appeared to have little impact in maintaining nor attenuating the stimulus effects of nicotine aerosol

Effects of paclitaxel on the development of neuropathy and affective behaviors in the mouse

Paclitaxel, one of the most commonly used cancer chemotherapeutic drugs, effectively extends the progression-free survival of breast, lung, and ovarian cancer patients. However, paclitaxel and other chemotherapy drugs elicit peripheral nerve fiber dysfunction or degeneration that leads to peripheral neuropathy in a large proportion of cancer patients. Patients receiving chemotherapy also often experience changes in mood, including anxiety and depression. These somatic and affective disorders represent major dose-limiting side effects of chemotherapy. Consequently, the present study was designed to develop a preclinical model of paclitaxel-induced negative affective symptoms in order to identify treatment strategies and their underlying mechanisms of action. Intraperitoneal injections of paclitaxel (8 mg/kg) resulted in the development and maintenance of mechanical and cold allodynia. Carboplatin, another cancer chemotherapeutic drug that is often used in combination with paclitaxel, sensitized mice to the nociceptive effects of paclitaxel. Paclitaxel also induced anxiety-like behavior, as assessed in the novelty suppressed feeding and light/dark box tests. In addition, paclitaxel-treated mice displayed depression-like behavior during the forced swim test and an anhedonia-like state in the sucrose preference test. In summary, paclitaxel produced altered behaviors in assays modeling affective states in C57BL/6J male mice, while increases in nociceptive responses were longer in duration. The characterization of this preclinical model of chemotherapy-induced allodynia and affective symptoms, possibly related to neuropathic pain, provides the basis for determining the mechanism(s) underlying severe side effects elicited by paclitaxel, as well as for predicting the efficacy of potential therapeutic interventions.United States Department of Health & Human Services National Institutes of Health (NIH) - USA - R01-CA206028VCU Massey Cancer CenterNIH-NCI Cancer Center Support Grant - P30 CA016059United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Cancer Institute (NCI) - R01CA206028 - P30CA01605

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