The debate about electronic cigarettes is dividing healthcare professionals, policymakers, manufacturers, and communities. A key limitation in our understanding of the cause and consequences of vaping is the lack of animal models of nicotine vapor self-administration. Here, we developed a novel model of voluntary electronic cigarette use in rats using operant behavior. We found that rats voluntarily exposed themselves to nicotine vapor to the point of reaching blood nicotine levels that are similar to humans. The level of responding on the active (nicotine) lever was similar to the inactive (air) lever and lower than the active lever that was associated with vehicle (polypropylene glycol/glycerol) vapor, suggesting low positive reinforcing effects and low nicotine vapor discrimination. Lever pressing behavior with nicotine vapor was pharmacologically prevented by the α4β2 nicotinic acetylcholine receptor partial agonist and α7 receptor full agonist varenicline in rats that self-administered nicotine but not vehicle vapor. Moreover, 3 weeks of daily (1 h) nicotine vapor self-administration produced addiction-like behaviors, including somatic signs of withdrawal, allodynia, anxiety-like behavior, and relapse-like behavior after 3 weeks of abstinence. Finally, 3 weeks of daily (1 h) nicotine vapor self-administration produced cardiopulmonary abnormalities and changes in α4, α3, and β2 nicotinic acetylcholine receptor subunit mRNA levels in the nucleus accumbens and medial prefrontal cortex. These findings validate a novel animal model of nicotine vapor self-administration in rodents with relevance to electronic cigarette use in humans and highlight the potential addictive properties and harmful effects of chronic nicotine vapor self-administration.
Rationale: Cannabidiol (CBD) reduces craving in animal models of alcohol and cocaine seeking and is known to modulate nicotinic receptor function, suggesting that it may alleviate symptoms of nicotine withdrawal; however, preclinical evaluation of its efficacy is still lacking. Objectives:The goal of this study was to test the preclinical efficacy of a chronic CBD treatment in reducing nicotine dependence using measures of withdrawal symptoms including somatic signs, hyperalgesia, and weight gain during acute and protracted abstinence.Methods: Male and female Wistar rats were made dependent on nicotine using osmotic minipumps (3.15 mg/kg/day) for two weeks, after which minipumps were removed to induce spontaneous withdrawal. Three groups received CBD injections at doses of 7.5, 15, and 30 mg/kg/day for two weeks, starting one week into chronic nicotine infusion. The control groups included rats with nicotine minipumps that received vehicle injections of sesame oil instead of CBD; rats implanted with saline minipumps that received sesame oil injections (double vehicle) or the highest dose of CBD 30mg/kg/day. Throughout the experiment, serum was collected for determination of CBD and nicotine concentrations, mechanical sensitivity threshold and withdrawal scores were measured, and body weight was recorded.Results: CBD prevented rats from exhibiting somatic signs of withdrawal and hyperalgesia during acute and protracted abstinence. There was no dose-response observed for CBD, suggesting a ceiling effect at the doses used and the potential for lower effective doses of CBD.The saline minipump group did not show either somatic signs of withdrawal or hyperalgesia during acute and protracted abstinence, and the highest dose of CBD used (30mg/kg/day) did not alter these results. 3Conclusions: This preclinical study suggests that using CBD as a strategy to alleviate the withdrawal symptoms upon nicotine-cessation may be beneficial.
Family and twin studies demonstrate that genetic factors determine 20-60% of the vulnerability to opioid use disorder. However, the genes/alleles that mediate the risk of developing addiction-related behaviors, including the sensitivity to the analgesic efficacy of opioids, the development of tolerance, dependence, and escalation of oxycodone taking and seeking, have been ill-defined, thus hindering efforts to design pharmacological interventions to enable precision medicine strategies. Here we characterized oxycodone addiction-like behaviors in heterogeneous stock (HS) rats, that show high genetic diversity that mimics the high genetic variability in humans. HS rats were allowed to self-administer oxycodone for two h/daily for four days (ShA) and then moved to 12h/daily (LgA) for 14 days. Animals were screened for motivation to self-administer oxycodone using a progressive-ratio (PR) schedule of reinforcement and for the development of withdrawal-induced hyperalgesia and tolerance to the analgesic effects of oxycodone using the von-Frey and tail immersion tests, respectively. To reduce cohort-specific effects, we used cohorts of 46-60 rats and normalized the response level within cohorts using a Z-score. To take advantage of the four opioid-related behaviors and further identify subjects that are consistently vulnerable vs. resilient to compulsive oxycodone use, we computed an Addiction Index by averaging normalized responding (Z-scores) for the four behavioral tests. Results showed high individual variability between vulnerable and resilient rats, likely to facilitate the detection of gene variants associated with vulnerable vs. resilient individuals. Such data will have considerable translational value for designing follow-up studies in humans.
The debate about electronic cigarettes has divided healthcare professionals, 15 policymakers, and communities. Central points of disagreement are whether vaping electronic cigarettes are addictive and whether they produce major pulmonary complications. We developed a novel model of nicotine vapor self-administration in rats and found that rats voluntarily exposed themselves to nicotine vapor to the point of reaching blood nicotine levels that are similar to humans, exhibiting both addiction-like behaviors and cardiopulmonary 20 abnormalities. The smoking cessation drug varenicline decreased electronic cigarette selfadministration. These findings confirm the addictive properties and harmful effects of nicotine vapor and identify a potential medication for the treatment of electronic cigarette addiction. One Sentence Summary:Vaping nicotine-containing electronic cigarettes produces cardiopulmonary abnormalities, nicotine dependence and addiction-like behaviors, which are 25 reduced by the smoking cessation drug varenicline.Main Text: Electronic cigarette use is exponentially increasing worldwide, particularly among adolescents. Between 2011 and 2015, high school students increased their electronic cigarette use by 900% (1). Electronic cigarettes are generally perceived to be safer than traditional cigarettes (2-4) because these devices do not burn tobacco to release nicotine but instead heat a 30 nicotine solution in the form of "vape juice," "e-juice," or "e-liquid." This liquid typically consists of propylene glycol and glycerin. It is often available in different flavors that appeal to both traditional cigarette smokers and non-smokers (5). However, our understanding of this relatively new nicotine delivery system and its long-term effects on human health is incomplete. Some in vitro models suggest that electronic cigarettes are safe (6, 7), whereas others suggest 35 that they may be harmful (8, 9). Little in vivo data are available to parse the short-and long-term effects of electronic cigarette use on addiction-like behaviors and pulmonary function (10). For example, it is unclear whether nicotine vapor is addictive, and there is no evidence that animals other than nonhuman primates will self-administer nicotine vapor to the point of developing addiction-like behaviors. Such information is critical to contribute to the social, political, and 40
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