Short-term effects of electronic and tobacco cigarettes on exhaled nitric oxide

The objective of this study was to compare the short-term respiratory effects due to the inhalation of electronic and conventional tobacco cigarette-generated mainstream aerosols through the measurement of the exhaled nitric oxide (eNO). To this purpose, twenty-five smokers were asked to smoke a conventional cigarette and to vape an electronic cigarette (with and without nicotine), and an electronic cigarette without liquid (control session).     

Ethanol self-administration and nicotine treatment increase brain levels of CYP2D in African green monkeys

BACKGROUND AND PURPOSE

CYP2D6 metabolizes many centrally acting drugs, neurotoxins and endogenous neurochemicals, and differences in brain levels of CYP2D have been associated with brain function and drug response. Alcohol consumers and smokers have higher levels of CYP2D6 in brain, but not liver, suggesting ethanol and/or nicotine may induce human brain CYP2D6. We investigated the independent and combined effects of chronic ethanol self-administration and nicotine treatment on CYP2D expression in African green monkeys.

EXPERIMENTAL APPROACH

Forty monkeys were randomized into control, ethanol-only, nicotine-only and ethanol + nicotine groups. Two groups voluntarily self-administered 10% ethanol in sucrose solution for 4 h·day⁻¹, whereas two groups consumed sucrose solution on the same schedule. Two groups received daily s.c. injections of 0.5 mg·kg⁻¹ nicotine in saline bid, whereas two groups were injected with saline on the same schedule.

KEY RESULTS

Both nicotine and ethanol dose-dependently increased CYP2D in brain; brain mRNA was unaffected, and neither drug altered hepatic CYP2D protein or mRNA. The combination of ethanol and nicotine increased brain CYP2D protein levels to a greater extent than either drug alone (1.2–2.2-fold, P < 0.05 among the eight brain regions assessed). Immunohistochemistry revealed the induction of brain CYP2D protein within specific cell types and regions in the treatment groups.

CONCLUSIONS AND IMPLICATIONS

Ethanol and nicotine increase brain CYP2D protein levels in monkeys, in a region and treatment-specific manner, suggesting that CNS drug responses, neurodegeneration and personality may be affected among people who consume alcohol and/or nicotine.     

Factors associated with weight changes in successful quitters participating in a smoking cessation program

Objective

To identify possible predictors of post-cessation weight gain in smoking abstainers.

Patients and methods

A sample of 607 successful abstainers seen at the Centre for Tobacco-Dependent in Prague, Czech Republic, between 2005 and 2010, was included in this analysis. This sample was followed up for 1 year and included 47.9% women (N = 291) with the mean age of 48 years (18–85).

Findings

Post-cessation weight gain occurred in 88.6% of the 607 abstainers. The mean weight gain after one year post-quit was 5.1 kg (95% confidence interval 4.7–5.5 kg). Baseline characteristics associated with increased weight gain included a higher baseline smoking rate (p < 0.001), more severe cigarette dependence (p = 0.003), less physical activity (p = 0.008), and a report of increased appetite on the baseline assessment of withdrawal symptoms (p < 0.001).

Conclusions

Smokers who are more dependent and have minimal physical activity are at increased risk for post-cessation weight gain. For these smokers, incorporating interventions targeting the weight issue into tobacco dependence treatment is recommended. Further research should be done to identify reasons for this important quitting complication.     

Diacylglycerol lipase disinhibits VTA dopamine neurons during chronic nicotine exposure

Chronic nicotine exposure (CNE) alters synaptic transmission in the ventral tegmental area (VTA) in a manner that enhances dopaminergic signaling and promotes nicotine use. The present experiments identify a correlation between enhanced production of the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) and diminished release of the inhibitory neurotransmitter GABA in the VTA following CNE. To study the functional role of on-demand 2-AG signaling in GABAergic synapses, we used 1,2,3-triazole urea compounds to selectively inhibit 2-AG biosynthesis by diacylglycerol lipase (DAGL). The potency and selectivity of these inhibitors were established in rats in vitro (rat brain proteome), ex vivo (brain slices), and in vivo (intracerebroventricular administration) using activity-based protein profiling and targeted metabolomics analyses. Inhibition of DAGL (2-AG biosynthesis) rescues nicotine-induced VTA GABA signaling following CNE. Conversely, enhancement of 2-AG signaling in naïve rats by inhibiting 2-AG degradation recapitulates the loss of nicotine-induced GABA signaling evident following CNE. DAGL inhibition reduces nicotine self-administration without disrupting operant responding for a nondrug reinforcer or motor activity. Collectively, these findings provide a detailed characterization of selective inhibitors of rat brain DAGL and demonstrate that excessive 2-AG signaling contributes to a loss of inhibitory GABAergic constraint of VTA excitability following CNE.The mesocorticolimbic dopamine (DA) system provides a critical link between the brain regions that process cognitive information and those controlling motor behavior. Precise control of these ventral tegmental area (VTA) projections facilitates seeking rewarding stimuli, retreating from aversive stimuli, constraint of motivational state, and behavioral flexibility necessary for survival. GABAergic signaling provides robust inhibition that gates VTA DA cell excitability (1, 2), and loss of this inhibition leads to pathological dysregulation of mesocorticolimbic circuitry (3, 4).Endocannabinoids (eCBs) regulate DAergic activity through retrograde signaling from DA cell bodies onto presynaptic cannabinoid type 1 (CB₁) receptors expressed on both inhibitory and excitatory inputs. Although both 2-arachidonoylglycerol (2-AG) and anandamide (AEA) function as endogenous CB₁ agonists in the brain (5–7), these lipids exhibit distinct pharmacological profiles in vivo (8, 9) and mediate differential behavioral effects (10, 11). Endocannabinoids are produced and degraded on-demand, and the primary enzymes responsible for eCB degradation have been well-characterized using selective pharmacological tools that inactivate monoacylglycerol lipase (MAGL) or fatty acid amide hydrolase (FAAH) (11–13). However, a complete evaluation of the influence of eCB signaling in the brain has been hampered by the lack of appropriate corresponding tools for selectively inactivating on-demand eCB biosynthesis.Substantial evidence implicates eCB signaling in the etiology of nicotine addiction, and recent work demonstrates that chronic nicotine exposure (CNE) selectively enhances nicotine-induced increases in VTA 2-AG formation (14). The present study investigated the possible contribution of this effect to aberrant VTA DA cell excitation present following CNE (15). We find that sensitized nicotine-induced 2-AG release (14) strongly correlates with a loss of nicotine-induced GABA release, which may contribute to impaired inhibitory constraint of VTA DA cell excitation following CNE. To test this hypothesis, we characterized a series of selective inhibitors of 2-AG biosynthesis by diacylglycerol lipase α and β (DAGLα and DAGLβ; hereafter referred to as DAGL) (16–18) and 2-AG degradation by α/β-hydrolase domain 6 (ABHD6) and MAGL (11, 12, 19), and used these compounds to investigate the functional impact of enhanced 2-AG recruitment on GABAergic signaling at VTA synapses and nicotine self-administration.     

基于内标微透析技术同步分析尼古丁透皮贴剂在血液与皮肤的药动学

目的：利用内标微透析采样技术,同步研究尼古丁透皮贴剂的血液和皮肤局部药动学特征,获得其较全面的体内药动学规律。方法：以健康SD大鼠为实验动物,将尼古丁透皮贴剂经皮给药,磷酸可待因作为微透析采样的内标物,采集不同时间点血液和皮肤微透析样品,用高效液相色谱法（HPLC）进行测定,利用DAS 2.1药动学软件计算相关药动学参数。结果：尼古丁在血液和皮肤的平均滞留时间（MRT_0-∞）分别为（16 986.00±486.00）min和（1 597.00±851.00）min,药时曲线下面积（AUC_0-∞）分别为（19 235.42±1 801.92）mg·mL^-1·min和（56 328.82±24 900.42）mg·mL^-1·min,达峰浓度（C_max）分别为（2.00±0.50）mg·L^-1和（32.00±5.00）mg·L^-1,达峰时间（t_max）分别为（325±200）min和（570±106）min。尼古丁在血液与皮肤的药动学参数相比,AUC_0-∞、C_max、t_max在皮肤中较大,MRT_0-∞在血液中较大。结论：尼古丁透皮贴剂经皮给药后,在血液与皮肤的药动学规律存在明显的差异与联系,药动学参数证明尼古丁通过透皮渗透在皮肤中以相对较高的浓度蓄积,能达到快速、有效的吸收,进入血液后血药浓度相对较低且维持稳定,发挥显著长效作用。     

Understanding the implications of the “vaping epidemic” among adolescents and young adults: A call for action

In the past 5 years, the use of nicotine delivered through electronic cigarettes (“e-cigarettes”) has sky-rocketed among adolescents and young adults. E-cigarettes, with their high nicotine content, appealing flavors, low costs, wide availability, and discreet designs threaten 5 decades of progress in the fight against tobacco use. Aside from the increased risk of subsequent use of traditional cigarettes, marijuana, opioids, and other illicit drugs, building evidence indicates that e-cigarette use also exposes youth to several acute and long-term health risks that greatly outweigh the as-yet unfounded potential benefits from the use of e-cigarettes as a smoking reduction or cessation tool in this age group. We discuss some of the latest research on e-cigarettes, highlighting risks and harms associated with their use in adolescents and young adults, and suggest opportunities for action, including the enforcement of age, sales and marketing limitations, and concerted research and public health efforts to help curb what has become a new nicotine epidemic among youth.     

不同浓度尼古丁对种植体骨愈合的影响

目的：探讨不同浓度的尼古丁干预,对种植体周围骨组织的愈合情况和骨保护素（OPG）及骨形成蛋白2（BMP-2）表达情况的影响。方法：选取24只3月龄SD大鼠,雌雄不限,随机数表法分为实验组和对照组,尔后分别采用不同浓度（2mg/kg、0.2mg/kg、0.02mg/kg）的尼古丁和等量生理盐水干预,每天2次背部皮下注射。2周后,大鼠左右胫骨近骺端均植入表面喷砂蚀刻处理的钛合金种植体,并继续施加干预因素。种植后第2、4周分别行X线、 CT、电镜观察和qRT-PCR检测。采用SPSS17.0软件对数据进行单因素方差分析（One-Way ANO-VA test）,组内比较行t检验。结果： X线灰度值显示,除高浓度尼古丁组（HDN）与对照组存在差异（P＜0.05）外,各组组间差异不明显。 CT-BMD值观察,在高浓度或长期尼古丁刺激下种植体周围骨组织矿化程度明显低于对照组,且实验各组差异明显（P＜0.05）。实时荧光定量PCR结果显示,2周时随着尼古丁干预浓度的增加,种植体周围基因表达量逐渐降低,且与对照组差异明显（P＜0.05）,仅低尼古丁浓度（LDN）组与对照组中的BMP-2的表达无明显差异（1/0.93＆#177;0.17, P＞0.05）;实验第4周,各尼古丁组的基因表达量均出现下调（P＜0.05）。扫描电镜（SEM）观察发现,随着尼古丁浓度和干预时间的增加,骨小梁结构发生改建障碍,多呈纤维骨或编织骨,骨基质分布不均匀且纤维结构排列紊乱无定向。结论：尼古丁对种植体周围骨愈合的抑制作用可能与其下调相关骨活性基因的表达关系密切,且抑制作用受尼古丁干预时间和浓度的影响明显。