Although menthol, a common flavoring additive to cigarettes, has been found to impact the addictive properties of nicotine cigarettes in smokers little is known about its pharmacological and molecular actions in the brain. Studies were undertaken to examine whether the systemic administration of menthol would modulate nicotine pharmacokinetics, acute pharmacological effects (antinociception and hypothermia) and withdrawal in male ICR mice. In addition, we examined changes in the brain levels of nicotinic receptors of rodents exposed to nicotine and menthol. Administration of i.p. menthol significantly decreased nicotine’s clearance (2-fold decrease) and increased its AUC compared to i.p. vehicle treatment. In addition, menthol pretreatment prolonged the duration of nicotine-induced antinociception and hypothermia (2.5 mg/kg, s.c.) for periods up to 180 min post-nicotine administration. Repeated administration of menthol with nicotine increased the intensity of mecamylamine-precipitated withdrawal signs in mice exposed chronically to nicotine. The potentiation of withdrawal intensity by menthol was accompanied by a significant increase in nicotine plasma levels in these mice. Western blot analyses of α4 and β2 nAChR subunit expression suggests that chronic menthol impacts the levels and distribution of these nicotinic subunits in various brain regions. In particular, co-administration of menthol and nicotine appears to promote significant increase in β2 and α4 nAChR subunit expression in the hippocampus, prefrontal cortex and striatum of mice. Surprisingly, chronic injections of menthol alone to mice caused an upregulation of β2 and α4 nAChR subunit levels in these brain regions. Because the addition of menthol to tobacco products has been suggested to augment their addictive potential, the current findings reveal several new pharmacological molecular adaptations that may contribute to its unique addictive profile.
Using a sample of 271 students from four schools in the southeast region of Missouri, this paper evaluates the impact of school resource officers (SRO) on young people's views and attitudes about the police and offending. The results suggest that the use of an SRO in schools does not change students' view of the police in general or offending. This weak impact is, at least in part, attributable to the negative contact that young people may have with the police and their SRO. This study concludes that, since the SRO has no significant impact on students' perception of police or offending, then it would behoove school administrators to utilize their financial resources for counseling, student-faculty crime prevention programs or delinquency awareness programs.
Background: E-cigarette use rates are high among youth, but there is limited information on the types of e-cigarette devices that are used by youth. Methods: During Spring 2017, students from 4 high schools completed surveys on use of e-cigarette devices (cig-a-like, vape/hookah pen, modified devices or mods, and JUUL). Among youth who endorsed ever (lifetime) use of an e-cigarette and of at least one device (n=875), we assessed 1) prevalence rates of ever and current (past-month) use of each device, 2) use of nicotine in each device, and 3) predictors [age, sex, race, socioeconomic status (SES), other tobacco use] of ever use of each device and of use of single versus multiple devices. Results: Cig-a-likes were used least frequently (Ever use: cig-a-likes: 25.4%; vape/hookah pens: 60.6%; JUUL: 64.2%; mods: 71.2%; Current use: cig-a-likes: 7.3%; vape/hookah pens; 18.7%; mods: 33.1%; JUUL: 47.1%;). Nicotine use was highest for JUUL (JUUL: 80.3%; mods: 56.3%; cig-a-likes: 51.4%; vape/hookah pens: 46.8%). Among ever users of single devices, use of JUUL was highest (JUUL: 43%; mods: 32%; vape/hookah pens: 21%; cig-a-likes: 4%). Ever use of all devices, except JUUL, was associated with other tobacco product use. Ever use of JUUL was associated with higher SES. Ever use of multiple devices (two: 34.7%; three: 25.8%; four: 11.7%) compared with a single device (27.8%) was associated with other tobacco product use. Conclusions: Targeted regulatory and prevention efforts that consider the use of multiple e-cigarette devices are needed to lower youth e-cigarette use rates.
Abuse of prescription opioids, such as oxycodone, has markedly increased in recent decades. While oxycodone’s antinociceptive effects have been detailed in several preclinical reports, surprisingly few preclinical reports have elaborated its abuse-related effects. This is particularly surprising given that oxycodone has been in clinical use since 1917. In a novel oral operant self-administration procedure, C57BL/6J mice were trained to self-administer water before introducing increasing concentrations of oxycodone (0.056–1.0 mg/ml) under post-prandial conditions during daily, 3-h test sessions. As the concentration of oxycodone increased, the numbers of deliveries first increased, then decreased in an inverted U-shape fashion characteristic of the patterns of other drugs self-administered during limited access conditions. After post-prandial conditions were removed, self-administration at the highest concentration was maintained suggesting oral oxycodone served as a positive reinforcer. In other mice, using a novel regimen of physical dependence, mice were administered increasing doses of oxycodone (9.0–33.0 mg/kg, s.c.) over 9 days, challenged with naloxone (0.1–10.0 mg/kg, s.c.), and then observed for 30 min. Naloxone dose-dependently increased the observed number of somatic signs of withdrawal, suggesting physical dependence of oxycodone was induced under this regimen. This is the first report demonstrating induction of oral operant self-administration of oxycodone and dose-dependent precipitations of oxycodone withdrawal in C57BL/6J mice. The use of oral operant self-administration as well as the novel physical dependence regimen provides useful approaches to further examine the abuse- and dependence-related effects of this highly abused prescription opioid.
Cigarette smokers with brain damage involving the insular cortex display cessation of tobacco smoking, suggesting that this region may contribute to nicotine addiction. In the present study, we speculated that molecules in the insular cortex that are sensitive to experimental traumatic brain injury (TBI) in mice might provide leads to ameliorate nicotine addiction. Using targeted lipidomics, we found that TBI elicited substantial increases of a largely uncharacterized lipid, N-acyl-glycine, N-oleoyl-glycine (OlGly), in the insular cortex of mice. We then evaluated whether intraperitoneal administration of OlGly would alter withdrawal responses in nicotine-dependent mice as well as the rewarding effects of nicotine, as assessed in the conditioned place preference paradigm (CPP). Systemic administration of OlGly reduced mecamylamine-precipitated withdrawal responses in nicotine-dependent mice and prevented nicotine CPP. However, OlGly did not affect morphine CPP, demonstrating a degree of selectivity. Our respective in vitro and in vivo observations that OlGly activated peroxisome proliferator-activated receptor alpha (PPAR-α) and the PPAR-α antagonist GW6471 prevented the OlGly-induced reduction of nicotine CPP in mice suggests that this lipid acts as a functional PPAR-α agonist to attenuate nicotine reward. These findings raise the possibility that the long chain fatty acid amide OlGly may possess efficacy in treating nicotine addiction.
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