Central nicotine induces browning through hypothalamic κ opioid receptor.

Increased body weight is a major factor that interferes with smoking cessation. Nicotine, the main bioactive compound in tobacco, has been demonstrated to have an impact on energy balance, since it affects both feeding and energy expenditure at the central level. Among the central actions of nicotine on body weight, much attention has been focused on its effect on brown adipose tissue (BAT) thermogenesis, though its effect on browning of white adipose tissue (WAT) is unclear. Here, we show that nicotine induces the browning of WAT through a central mechanism and that this effect is dependent on the κ opioid receptor (KOR), specifically in the lateral hypothalamic area (LHA). Consistent with these findings, smokers show higher levels of uncoupling protein 1 (UCP1) expression in WAT, which correlates with smoking status. These data demonstrate that central nicotine-induced modulation of WAT browning may be a target against human obesity.

Exploration of the wound healing effect of topical administration of nicotine in combination with collagen scaffold in a rabbit model.

Nicotine has been reported to prolong the wound healing; however, we showed that the topical application of 10(-4) M nicotine promoted murine wound healing. The objective of this study was to explore the wound healing effects of nicotine in combination with collagen scaffold using skin defects in rabbit. Three full-thickness skin defects 8 mm in diameter were made on the rabbit auricle. Artificial dermis was applied to the defects, and 10 µl of nicotine solution (10(-5), 10(-4), and10(-3) M), bFGF solution (0.5 µg/10 µl), and both bFGF and 10(-4) M nicotine solutions were injected into the artificial dermis once daily for 7 days. Rabbits were sacrificed on day 10, 15, or 20, and the wound healing process was evaluated. bFGF was superior in the formation of the dermis-like tissue and capillaries. In nicotine groups, the epithelial length and the dermis-like tissue formations in the 10(-4) M group were superior, in contrast, those were inhibited in the 10(-3) M group. The synergistic effect of bFGF and 10(-4) M nicotine was not confirmed. This study suggests that the topical application of 10(-4) M nicotine promoted wound healing in rabbit, but the effect was not apparent compared with murine models.

Chronic nicotine treatment enhances vascular smooth muscle relaxation in rats.

AIM: To investigate the effect of chronic nicotine treatment on vascular function and to identify the underlying mechanisms. METHODS: Adult rats were treated with nicotine (3 mg·kg(-1)·d(-1), sc) for 6 weeks. After the rats were sacrificed, aortic rings were prepared for detecting vascular reactivity, and thoracic aorta and periaortic fat samples were collected for histological and molecular biology studies. RESULTS: Chronic nicotine treatment significantly reduced periaortic fat, and specifically enhanced smooth muscle relaxation without altering the aortic adventitial fat and endothelium function. Pretreatment with the soluble guanylyl cyclase inhibitor ODQ (3 µmol/L) or PKG inhibitor Rp-8-Br-PET-cGMP (30 µmol/L) abolished the nicotine-induced enhancement of smooth muscle relaxation, whereas the cGMP analogue 8-Br-cGMP could mimic the nicotine-induced enhancement of smooth muscle relaxation. However, the chronic nicotine treatment did not alter PKG protein expression and activity in aortic media. CONCLUSION: Chronic nicotine treatment enhances vascular smooth muscle relaxation of rats via activation of PKG pathway.

Vitamin C supplementation ameliorates the adverse effects of nicotine on placental hemodynamics and histology in nonhuman primates.

OBJECTIVE: We previously demonstrated that prenatal nicotine exposure decreases neonatal pulmonary function in nonhuman primates, and maternal vitamin C supplementation attenuates these deleterious effects. However, the effect of nicotine on placental perfusion and development is not fully understood. This study utilizes noninvasive imaging techniques and histological analysis in a nonhuman primate model to test the hypothesis that prenatal nicotine exposure adversely effects placental hemodynamics and development but is ameliorated by vitamin C. STUDY DESIGN: Time-mated macaques (n = 27) were divided into 4 treatment groups: control (n = 5), nicotine only (n = 4), vitamin C only (n = 9), and nicotine plus vitamin C (n = 9). Nicotine animals received 2 mg/kg per day of nicotine bitartrate (approximately 0.7 mg/kg per day free nicotine levels in pregnant human smokers) from days 26 to 160 (term, 168 days). Vitamin C groups received ascorbic acid at 50, 100, or 250 mg/kg per day with or without nicotine. All underwent placental dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) at 135-140 days and Doppler ultrasound at 155 days to measure uterine artery and umbilical vein velocimetry and diameter to calculate uterine artery volume blood flow and placental volume blood flow. Animals were delivered by cesarean delivery at 160 days. A novel DCE-MRI protocol was utilized to calculate placental perfusion from maternal spiral arteries. Placental tissue was processed for histopathology. RESULTS: Placental volume blood flow was significantly reduced in nicotine-only animals compared with controls and nicotine plus vitamin C groups (P = .03). Maternal placental blood flow was not different between experimental groups by DCE-MRI, ranging from 0.75 to 1.94 mL/mL per minute (P = .93). Placental histology showed increased numbers of villous cytotrophoblast cell islands (P < .05) and increased syncytiotrophoblast sprouting (P < .001) in nicotine-only animals, which was mitigated by vitamin C. CONCLUSION: Prenatal nicotine exposure significantly decreased fetal blood supply via reduced placental volume blood flow, which corresponded with placental histological findings previously associated with cigarette smoking. Vitamin C supplementation mitigated the harmful effects of prenatal nicotine exposure on placental hemodynamics and development, suggesting that its use may limit some of the adverse effects associated with smoking during pregnancy.

The effect of hyperbaric oxygen treatment on the healing of burn wounds in nicotinized and nonnicotinized rats.

The importance of oxygen in wound healing and the negative effects of cigarette smoking have been demonstrated in various studies. In this study, our aim was to investigate the effect of hyperbaric oxygen (HBO2) treatment on wound healing in nicotinized and nonnicotinized rats. The study was conducted on 32 Sprague Dawley rats. The rats were divided into four groups, with eight rats in each: group 1, nonnicotinized rats; group 2, nonnicotinized rats treated with HBO2; group 3, nicotinized rats; and group 4, nicotinized rats treated with HBO2. To prepare the nicotinized groups, the rats were given nicotine for 28 days. At the end of day 28, standard, deep, second-degree to third-degree burns were created on the rats. The HBO2-treated groups underwent HBO2 treatment once a day for 7 days after the creation of the burn damage. All rats were killed 21 days after injury, and the burns were subjected to macroscopic, histopathological, and microbiological evaluation. During this evaluation, the smallest necrotic areas and the lowest rate of fibrosis were observed in group 2. The largest necrotic areas and the highest inflammation and fibrosis rates were observed in the nicotine-treated group 3. When the nicotinized and nonnicotinized groups were compared separately, there was a significant difference in favor of the groups treated with HBO2. Bacterial growth was the highest in the nicotinized group 3, whereas no statistically significant difference was observed among the other groups. We conclude that HBO treatment accelerates the recovery of burn wounds and provides more effective healing by reducing the development of scars both in nicotinized and nonnicotinized rats.

Menstrual cycle and cue reactivity in women smokers.

INTRODUCTION: Emerging research suggests potential effects of the menstrual cycle on various aspects of smoking behavior in women, but results to date have been mixed. The present study sought to explore the influence of menstrual cycle phase on reactivity to smoking in vivo and stressful imagery cues in a sample of non-treatment-seeking women smokers. METHODS: Via a within-subjects design, nicotine-dependent women (N = 37) participated in a series of four cue reactivity sessions, each during a distinct biologically verified phase of the menstrual cycle (early follicular [EF], mid-follicular [MF], mid-luteal [ML], and late luteal [LL]). Subjective (Questionnaire of Smoking Urges-Brief; QSU-B) and physiological (skin conductance and heart rate) measures of craving and reactivity were collected and compared across phases. RESULTS: Subjective reactive craving (QSU-B) to smoking in vivo cues varied significantly across the menstrual cycle (p = .02) and was higher in both EF and MF phases versus ML and LL phases, but this finding was not sustained when controlling for reactivity to neutral cues. Heart rate reactivity to stressful imagery cues (p = .01) and skin conductance reactivity to smoking in vivo cues (p = .05) varied significantly across the menstrual cycle upon controlling for reactivity to neutral cues, with highest reactivity during the MF phase. DISCUSSION: Menstrual cycle phase may have an effect on reactivity to smoking-related and stressful cues among women smokers. These findings contribute to an expanding literature, suggesting menstrual cycle effects on smoking behaviors in women.

Hypnosis for smoking cessation: a randomized trial.

The purpose of this study was to determine whether hypnosis would be more effective in helping smokers quit than standard behavioral counseling when both interventions are combined with nicotine patches (NP). A total of 286 current smokers were enrolled in a randomized controlled smoking cessation trial at the San Francisco Veterans Affairs Medical Center. Participants in both treatment conditions were seen for two 60-min sessions, and received three follow-up phone calls and 2 months of NP. At 6 months, 29% of the hypnosis group reported 7-day point-prevalence abstinence compared with 23% of the behavioral counseling group (relative risk [RR] = 1.27; 95% confidence interval, CI 0.84-1.92). Based on biochemical or proxy confirmation, 26% of the participants in the hypnosis group were abstinent at 6 months compared with 18% of the behavioral group (RR = 1.44; 95% CI 0.91-2.30). At 12 months, the self-reported 7-day point-prevalence quit rate was 24% for the hypnosis group and 16% for the behavioral group (RR = 1.47; 95% CI 0.90-2.40). Based on biochemical or proxy confirmation, 20% of the participants in the hypnosis group were abstinent at 12 months compared with 14% of the behavioral group (RR = 1.40; 95% CI 0.81-2.42). Among participants with a history of depression, hypnosis yielded significantly higher validated point-prevalence quit rates at 6 and 12 months than standard treatment. It was concluded that hypnosis combined with NP compares favorably with standard behavioral counseling in generating long-term quit rates.

Thalamic microinjection of nicotine reverses sevoflurane-induced loss of righting reflex in the rat.

BACKGROUND: Neuronal nicotinic acetylcholine receptors are both potently inhibited by anesthetics and densely expressed in the thalamus. Brain imaging shows that thalamic activity suppression accompanies anesthetic-induced unconsciousness. Therefore, anesthetic-induced unconsciousness may involve direct antagonism of thalamic nicotinic receptors. The authors test this by separately attempting to block or enhance anesthetic-induced loss of righting in rats using intrathalamic microinjections of nicotine or its antagonist. METHODS: Rats were implanted with a cannula aimed at the thalamus or control locations. A week later, loss of righting was induced using sevoflurane (1.4 +/- 0.2%). A dose-parameter study (n = 35) first identified an optimal intrathalamic nicotine dose associated with arousal. Subsequently, this dose was used to pinpoint the thalamic site mediating the arousal response (n = 107). Finally, sevoflurane righting dose and response specificity were assessed after blocking nicotinic channels with intrathalamic mecamylamine pretreatment (n = 8) before nicotine challenge. RESULTS: Nicotine (150 microg/0.5 microl over 1 min) was the optimal arousal dose, because lower doses (75 microg) were ineffective and higher doses (300 microg) often caused seizures. Nicotine temporarily restored righting and mobility in animals when microinjections involved the central medial thalamus (P < 0.0001, chi-square). Righting occurred despite continued sevoflurane administration. Intrathalamic mecamylamine pretreatment did not lower the sevoflurane dose associated with loss of righting, but prevented the nicotine arousal response. CONCLUSIONS: The reversal of unconsciousness found here with intrathalamic microinfusion of nicotine suggests that suppression of the midline thalamic cholinergic arousal system is part of the mechanism by which anesthetics produce unconsciousness.

Effects of nicotine and vitamin E on glutathione reductase activity in some rat tissues in vivo and in vitro.

Effects of nicotine, and nicotine+vitamin E on glutathione reductase (Glutathione: NADP(+) oxidoreductase, EC 1.8.1.7) activity in the muscle, heart, lungs, testicles, kidney, stomach, brain and liver tissues were investigated in vivo and also in vitro. The groups were: nicotine [0.5 mg/kg/day, intraperitoneal (i.p.)]; nicotine+vitamin E [75 mg/kg/day, intragastric (i.g.)]; and control group (receiving only vehicles). There were eight rats per group and supplementation period was 3 weeks. The results showed that nicotine (0.5 mg/kg, i.p.) inhibited glutathione reductase activity significantly in the liver, lungs, heart, stomach, kidney, and testicles by approximately 61.5%, approximately 65%, approximately 70.5%, approximately 72.5%, approximately 64% and approximately 71.5%, respectively, while it had activated glutathione reductase activity in the brain by approximately 11.8%, and had no effect on the muscle glutathione reductase activity. Vitamin E supplementation prevented this nicotine-induced decrease in glutathione reductase activity in liver, lungs, heart, stomach, and kidney. However, it did not prevent this nicotine-induced decrease in testicles. In vitro studies were also carried out to elucidate the effects of nicotine and vitamin E on glutathione reductase activity. In vitro results correlated well with in vivo experimental results in liver, lungs, heart, stomach, and testicular tissues. These results show that vitamin E administration generally restores the inactivation of glutathione reductase activity due to nicotine administration in various rat tissues in vivo, and also in vitro.

Mild anxiogenic effects of nicotine withdrawal in mice.

Increased anxiety is one of the symptoms of nicotine withdrawal that may lead to relapse. Previous studies have shown that nicotine withdrawal affects anxiety-like behavior in different tests of anxiety in humans and rats. However, relatively few studies have focused on the anxiogenic effect of nicotine withdrawal in mice. The present study investigated the effect of nicotine withdrawal on anxiety-like behavior in DBA/2J and C57BL/6J mouse strains in the light-dark box, acoustic startle response, and prepulse inhibition tests. An initial experiment showed that nicotine administration of 12 or 24 mg/kg/day (free base) for 14 days did not result in significant effects during withdrawal in startle, prepulse inhibition, or light-dark box, but there was a trend towards an anxiogenic effect in the light-dark box 24 h, but not 1 or 4 h, after cessation of nicotine administration. A subsequent study was therefore performed, with minipumps delivering saline, 24 mg/kg/day nicotine, or 48 mg/kg/day nicotine (free base), for 14 days. The pumps were removed, and the mice were tested 24 h after cessation of nicotine administration. Cessation of administration of 48 mg/kg/day nicotine free base in C57BL/6J mice resulted in increased anxiety-like behavior in the light-dark box, while the behavior of DBA/2J mice was unaffected. The acoustic startle response and prepulse inhibition were also unaffected in both strains. In conclusion, the present data show that nicotine withdrawal is mildly anxiogenic in C57BL/6J mice under the conditions used in the present experiments.

Nicotine induced inhibition of the activities of accessory reproductive ducts in male rats.

Adult male albino rats were treated with 0.4 mg nicotine/100 g body weight either orally or intraperitoneally for 30 days. All animals were autopsied on the 31st day. Epididymis and vas deferens were dissected out, weighed and processed for biochemical estimations. Nicotine caused a reduction in the weight of epididymis and vas deferens in both drug treated groups. The total cholesterol content is increased while protein, DNA and RNA contents and the epididymal sperm count were decreased. The acid phosphatase content is also decreased, whereas alkaline phosphatase is increased. The surface epithelial cell height of these ducts is decreased and secretory activity is reduced with the disruption of epithelial cell projections. These changes may be due to non-availability of androgens in nicotine treated rats.

Mechanism of intragastric tetramethylammonium protection against 40% ethanol injury in rat stomach.

The effect of tetramethylammonium (TMA), a ganglionic stimulant, on gastric mucosal injury induced by 40% ethanol was examined. In studies I-III, rats were treated with intragastric vehicle or TMA (1 or 10 mg/kg). In study I, 1 hr after the treatment, 40% ethanol was given intragastrically. The length of the linear corpus mucosal lesions was measured unbiasedly with a caliper after another hour. In study II, mean blood pressure was assessed before and after the treatment. In study III, 1 hr after the treatment, gastric mucus and juice volumes, and titratable acid were measured. In study IV, 40% ethanol (10 ml/kg) was administered intragastrically immediately after 0.2 or 1.4 ml of intragastric vehicle treatment. One hour later, gastric lesions score was assessed as in study I. Results show that (1) intragastric TMA dose-dependently protected against 40% ethanol-induced gastric injury; (2) neither dose of intragastric TMA increased mean blood pressure; (3) there was a dose-related increase in gastric mucus secretion for TMA 1 and 10 mg/kg, and a significant increase in gastric juice volume only for TMA 10 mg/kg; and (4) the rats treated with 1.4 ml of vehicle plus 40% ethanol had significantly less injury than those treated with 0.2 ml of vehicle plus 40% ethanol. We conclude that the protective effect of intragastric TMA can be explained by its dose-related effect in enhancing gastric mucus secretion for TMA 1 and 10 mg/kg and the significantly greater increase in gastric juice volume for TMA 10 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Locomotor activity in rats after administration of nicotinic agonists intracerebrally.

1. Nicotine (0.13 and 0.4 mg kg-1, s.c.) increased the ambulatory component of locomotor activity in rats previously exposed to the drug. Nicotine did not increase repeated movements reliably. 2. An infusion of either nicotine (8 micrograms) or the potent nicotinic agonist cytisine (4 micrograms) into the ventral tegmental area of the forebrain increased ambulation but not repeated movements. 3. An infusion of nicotine or cytisine into the nucleus accumbens, striatum, dorsal hippocampal formation or motor thalamus did not increase ambulatory or repeated movements. 4. Mecamylamine (0.1-1.0 mg kg-1, s.c.) blocked increases in locomotor activity produced by an infusion of nicotine or cytisine into the ventral tegmental area. 5. The locomotor activity produced by systemically administered nicotine may be mediated, in part, through nicotinic receptors located in the ventral tegmental area of the mesolimbic dopamine system.