尼古丁对大鼠海洛因辨别刺激的替代效应

目的 在建立大鼠海洛因辨别刺激模型基础上,评估不同浓度的尼古丁对海洛因辨别刺激的替代作用.方法 采用固定比率食物强化方法训练雄性SD大鼠辨别0.3 mg/kg海洛因；之后,分别给予不同剂量的海洛因、尼古丁替代0.3 mg/kg海洛因,明确海洛因辨别效应曲线和尼古丁替代0.3 mg/kg海洛因的辨别效应.结果 0.3 mg/kg剂量的海洛因能形成稳定的大鼠药物辨别行为；不同剂量海洛因替代组(0.03,0.1,0.3,0.56 mg/kg)的海洛因鼻触响应率分别为(33.9±15.0)％,(43.3±13.3)％,(98.7±0.5)％,(99.4±0.2)％,海洛因剂量在0～0.3mg/kg之间诱导的辨别效应呈剂量依赖性增加；0.03,0.1mg／kg尼古丁替代组的海洛因鼻触响应率分别为(1.9±1.1)％,(13.7±5.6)％,与0.3mg/kg海洛因替代组相比,差异有统计学意义(P＜0.01)；而0.3,0.5mg/kg尼古丁替代组的海洛因鼻触响应率分别为(60.4±16.1)％,(65.9±16.4)％,与0.3mg/kg海洛因替代组相比,差异无统计学意义(P＞0.05).结论 0.3,0.5 mg/kg尼古丁能产生部分类似海洛因的辨别刺激效应.     

Nicotine Self-Administration in Animals: A Reevaluation

Nicotine self-administration in animals is often viewed as compelling evidence that nicotine is reinforcing to animals and as corroborating the widely accepted thesis that nicotine is a major cause of smoking. This review examines the studies of nicotine self-administration in animals in the past two decades, focusing on threats to the internal and external validity of these studies and on the extent to which they support the thesis that nicotine is reinforcing in animals. The review shows that nicotine self-administration studies are fraught with severe methodological problems. These include omission of essential controls for general activation and other systemic effects of nicotine, insufficient consideration of secondary reinforcement processes, using food-deprived or confined animals and exclusion of subjects that do not conform to the investigators' preferred behavior. As a result of these systematic flaws, the role of nicotine as a reinforcer in this paradigm has not been established.     

Nicotinic modulation of salience network connectivity and centrality in schizophrenia

Although functional abnormalities of the salience network are associated with schizophrenia, the acute effects of nicotine on its function and network dynamics during the resting state in patients are poorly understood. In this study, the effects of a 7 mg nicotine patch (vs. placebo) on salience network connectivity were examined in 17 patients with schizophrenia and 19 healthy subjects. We hypothesized abnormal connectivity between the salience network and other major networks (e.g. executive network) in patients under placebo administration and amelioration of this difference after nicotine. We also examined effects of nicotine on betweenness centrality (a measure of the influence of a region on information transfer throughout the brain) and local efficiency (a measure of local information transfer) of the network. A hybrid independent component analysis (ICA)/seed-based connectivity approach was implemented in which the salience network was extracted by ICA and cortical network peaks (anterior cingulate cortex (ACC), left and right insula) were used as seeds for whole-brain seed-to-voxel connectivity analysis. Significant drug X diagnosis interactions were observed between the ACC seed and superior parietal lobule and ventrolateral prefrontal cortex. A significant interaction effect was also observed between the left insula seed and middle cingulate cortex. During placebo conditions, abnormal connectivity predicted negative symptom severity and lower global functioning in patients. A significant drug X diagnosis interaction was also observed for betweenness centrality of the ACC. These results suggest that nicotine may target abnormalities in functional connectivity between salience and executive network areas in schizophrenia as well as affect the ability of the salience network to act as an integrator of global signaling in the disorder.     

Folic acid protects against experimental prenatal nicotine–induced cardiac injury by decreasing inflammatory changes,serum TNF and COX-2 expression

Nicotine administration has been shown to increase the risk for cardiovascular diseases and death. The present study was designed to investigate the impact of nicotine administration on serum level tumor necrosis factor and cycloxygenase -2 (COX-2) expression mediated cardiac injury in rat off springs, and the possible protective effect of folic acid. Eighteen pregnant female rats were randomly divided into three groups, six animals each. Control group received the vehicle, nicotine group received a dose of nicotine 0.1?mg/kg body weight, daily with subcutaneous injection from day 3 of gestation until weaning on postnatal day 21. Nicotine treated group received daily oral supplementation with folic acid 200?mg/kg body weight by intragastric tube prior to injection of nicotine. In serum of the pups, levels of tumor necrosis factor (TNF), nitric oxide (NO), total antioxidant capacity (TAC) and malondialdehyde (MDA) were measured. Histopathological studies of cardiac tissues using hematoxylin-eosin (H&E) were carried out. The expression of COX-2 was evaluated using immunohistochemistry. Serum TNF and MDA were significantly increased, while serum NO and TAC were significantly decreased in nicotine group. Moreover, nicotine-exposed rats showed complete lysis of cardiac myocytes, marked cytoplasmic vacuolation of myocytes, muscle fibers show loss of striation and increased COX-2 expression. Concomitant folic acid administration resulted in a significant alleviation of biochemical and structural alteration-induced by nicotine. In conclusion, folic acid has a protective role against nicotine induced cardiac injury by reduction of COX-2 expression, decreasing TNF production and lipid peroxidation mediated cell injury.     

Nicotine does not affect stem cell properties requisite for suicide gene therapy against glioma

ABSTRACT

Objective: 

Glioblastoma is one of the most lethal tumors in adult central nervous system with a median survival of a year and half and effective therapeutic strategy is urgently needed. For that reason, stem cell-based suicide gene therapies have attracted much interest because of potent tumor tropism of stem cells and bystander effect. In this current clinical situation, stem cells are promising delivery tool of suicide genes for glioma therapy. Since habitual cigarette smoking still prevails worldwide, we investigated the effect of nicotine on stem cell tropism toward glioma and gap junctional intercellular communication (GJIC) function between glioma and stem cells, both of which are important for suicide gene therapies. Methods: Mouse induced pluripotent stem cell-derived neural stem cells (iPS-NSCs) and human dental pulp mesenchymal stem cells (DPSCs) were used. The effect of nicotine on tumor tropism to glioma-conditioned medium (CM) at a non-cytotoxic concentration was assessed with Matrigel invasion assay. Nicotine effect on GJIC was assessed with the scrape loading/dye transfer (SL/DT) assay for co-culture of glioma and stem cells and the parachute assay among glioma cells using high-content analysis. Results: Tumor tropism of iPS-NSCs toward GL261-CM and DPSCs toward U251-CM was not affected by nicotine (0.1 and 1 µM). Nicotine at the concentrations equivalent to habitual smoking (1 µM) did not affect GJIC of iPS-NSC/GL261 and DPSC/U251 and GJIC among each glioma cells. Conclusions: The study demonstrated that non-cytotoxic concentrations of nicotine did not significantly change the stem cell properties requisite for stem cell-based suicide gene therapy.     

Aortic Remodelling in Chronic Nicotine-Administered Rat

Vascular remodelling is an adaptive mechanism, which counteracts pressure changes in blood circulation. Nicotine content in cigarette increases the risk of hypertension. The exact relationship between nicotine and vascular remodelling still remain unknown. Current study was aimed to determine the effect of clinically relevant dosage of nicotine (equivalent to light smoker) on aortic reactivity, oxidative stress markers and histomorphological changes. Twelve age-matched male Sprague-Dawley rats were randomly divided into two groups, i.e.: normal saline as control or 0.6 mg/kg nicotine for 28 days (i.p., n=6 per group). On day-29, the rats were sacrificed and the thoracic aorta was dissected immediately for further studies. Mean arterial pressure (MAP) and pulse pressure (PP) of nicotine-treated vs. control were significantly increased (p<0.05). Nicotine-treated group showed significant (p<0.05) increase tunica media thickness, and decrease in lumen diameter, suggesting vascular remodelling which lead to prior hypertension state. The phenylephrine (PE)-induced contractile response in nicotine group was significantly higher than control group (ED₅₀=1.44×10⁵ M vs. 4.9×10⁶ M) (p<0.05~0.001). However, nicotine-treated rat showed significantly lower endothelium-dependent relaxation response to acetylcholine (ACh) than in control group (ED₅₀=6.17×10⁷ M vs. 2.82×10⁷ M) (p<0.05), indicating loss of primary vascular function. Malondialdehyde (MDA), a lipid peroxidation marker was significantly higher in nicotine group. Superoxide dismutase (SOD) enzymatic activity and glutathione (GSH) were all reduced in nicotine group (p<0.05) vs. control, suggesting nicotine induces oxidative imbalance. In short, chronic nicotine administration impaired aortic reactivity, probably via redox imbalance and vascular remodelling mechanism.     

Gender differences in characteristics and outcomes of smokers diagnosed with psychosis participating in a smoking cessation intervention

While research has identified gender differences in characteristics and outcomes of smokers in the general population, no studies have examined this among smokers with psychosis. This study aimed to explore gender differences among 298 smokers with psychosis (schizophrenia, schizoaffective and bipolar affective disorder) participating in a smoking intervention study. Results revealed a general lack of gender differences on a range of variables for smokers with psychosis including reasons for smoking/quitting, readiness and motivation to quit, use of nicotine replacement therapy, and smoking outcomes including point prevalence or continuous abstinence, and there were no significant predictors of smoking reduction status according to gender at any of the follow-up time-points. The current study did find that female smokers with psychosis were significantly more likely than males to report that they smoked to prevent weight gain. Furthermore, the females reported significantly more reasons for quitting smoking and were more likely to be driven by extrinsic motivators to quit such as immediate reinforcement and social influence, compared to the male smokers with psychosis. Clinical implications include specifically focussing on weight issues and enhancing intrinsic motivation to quit smoking for female smokers with psychosis; and strengthening reasons for quitting among males with psychosis.