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PubMed2004

Nitric oxide is involved in nicotine-induced burst firing of rat ventral tegmental area dopamine neurons.

In the present study, using single cell recordings in vivo and intracellular recordings in vitro from midbrain slices, the role of N-methyl-d-aspartate (NMDA) receptor signaling on firing activity in ventral tegmental area dopamine neurons elicited by nicotine was investigated in the rat. In accordance with previous studies, systemic nicotine (0.5 mg/kg s.c.) increased both firing rate and burst firing of dopamine neurons in vivo, and bath-applied nicotine (10 microM) increased firing rate in vitro. The competitive NMDA receptor antagonist CGP39551 (2.5 mg/kg i.p.) inhibited nicotine's effects on burst firing and also attenuated the nicotine-induced increase in firing rate. Moreover, although the nitric oxide (NO)-synthase inhibitor N-nitro-l-arginine-methyl-ester (l-NAME; 5.0 mg/kg i.p.) had no effect on cell firing by itself, it prevented the response to nicotine in vivo. In contrast, l-NAME (100 microM) did not influence nicotine's effect on dopamine cell firing in vitro, suggesting that the effect of l-NAME seen in vivo is dependent on presynaptic afferent input. The present study confirms previous results suggesting that the effect of systemically administered nicotine is in part presynaptic and mediated via NMDA receptors. The data also indicate that NO plays an important role in the previously demonstrated, indirect, glutamate-mediated excitation of these neurons by nicotine. By inference, our results provide additional support for the involvement of NO in nicotine dependence.

2-Amino-5-phosphonovalerate↗
PubMed2006

Immediate and long-term behavioral effects of a single nicotine injection in adolescent and adult rats.

We examined the acute rewarding as well as the long-term psychomotor altering effects of nicotine in early adolescent and adult male Sprague-Dawley rats. Place conditioning was used to examine nicotine-induced reward after a single drug pairing. A single pairing of nicotine with the initially non-preferred side of the place conditioning apparatus produced a conditioned place preference (CPP) in early adolescent but not adult animals. One month later, animals were given a nicotine challenge and locomotor activity observed in the open field to characterize age differences in the lasting alterations resulting from this single injection. Adult rats showed tolerance to the locomotor depressant effects of a low dose of nicotine whereas adolescent rats showed tolerance to a higher dose. Regardless of treatment group, animals tested during adolescence responded to the nicotine challenge with less hypoactivity when compared with animals tested as adults. The present results are in agreement with previous studies showing that early adolescent rats are more sensitive to nicotine's rewarding effects and are in accord with studies showing a unique profile of neurobehavioral alterations following nicotine exposure when compared with adults. Such findings are extended here by showing that these differences are seen following only a single pretreatment dose and persist for at least one month after pretreatment.

Age Factors↗
PubMed2005

Nicotine pretreatment diminished physostigmine-induced tremor in rats.

The aim of this work was evaluate the effects of acute and chronic nicotine pretreatment in the physostigmine-induced tremor in rats. Wistar male rats (3-4 months) were pretreated acutely with different nicotine doses (0, 0.1, 0.5 or 1.0 mg/kg) 10 min before physostigmine (0 and 0.5 mg/kg) treatment and then the tremor was registered by computerized system for 10 min. In another group, rats were pretreated acutely with 0.1 mg/kg of nicotine, recovered at different times (30 or 70 min), and were registered for physostigmine-induced tremor. Nicotine was also used chronically with equal doses for 8 days and recovered at 2, 7 or 21 days before registration of physostigmine-induced tremor. Tremor spectral analysis was performed for amplitude and frequency quantification. Our data show that the acute and chronic nicotine pretreatments alter physostigmine spectrum profile. Nicotine decreased physostigmine-induced tremor amplitude (p<0.05), without changing its tremor frequency. In acutely pretreated rats, recovery experiments showed return of physostigmine-induced tremor for control levels after 70 min, but after 8 days of chronic nicotine pretreatment recovery was delayed 3 weeks. The data analysis shows that acute or chronic nicotine administration can alleviate the physostigmine-induced tremor. Chronic nicotine pretreatment has a long tremor alleviation effect of physostigmine-induced tremor. Possible mechanisms involving the nicotine effects on the physostigmine-induced tremor are discussed.

Animals↗
PubMed2005

The airway sensory impact of nicotine contributes to the conditioned reinforcing effects of individual puffs from cigarettes.

Puffs from cigarettes are the fundamental unit of smoking reward. Here, we examined the extent to which reward from puffs can be derived from the airway sensory effect of nicotine, in the absence of a direct central nervous system effect of nicotine. We did this by assessing the self-reported reward obtained from individual puffs from nicotinized, denicotinized and unlit cigarettes within 7 s of inhalation, which is before nicotine had an opportunity to reach the brain. We also assessed the self-reported strength of airway sensations elicited by the puffs. We found that nicotinized puffs were rated as both stronger and more rewarding than denicotinized and unlit puffs. We also found that the extent to which nicotine elicited reward was directly correlated with the extent to which nicotine elicited airway sensations. This indicates that the airway sensory effects of nicotine contribute to the reward from puffs, above and beyond the reward derived from the airway sensory effects of non-nicotine constituents. These findings have implications for the interpretation of studies that use puffs as experimental units to examine nicotine reward. They also have implications for the use of denicotinized and low nicotine cigarettes as aids to smoking cessation.

Adult↗
PubMed2006

Nicotine activates cell-signaling pathways through muscle-type and neuronal nicotinic acetylcholine receptors in non-small cell lung cancer cells.

Nicotinic acetylcholine receptors (nAChR) are expressed on non-neuronal cell types, including normal bronchial epithelial cells, and nicotine has been reported to cause Akt activation in cultured normal airway cells. This study documents mRNA and protein expression of subunits known to form a muscle-type nAChR in non-small cell lung cancer (NSCLC) cell lines. In one NSCLC examined, mRNA and protein for a heteropentamer neuronal-type alpha3beta2 nAChR was detected in addition to a muscle-type receptor. Protein for the alpha5 nAChR was also detected in NSCLC cells. Although, mRNA for the alpha7 nAChR subunit was observed in all cell lines, alpha7 protein was not detectable by immunoblot in NSCLC cell extracts. Immunohistochemistry (IHC) of NSCLC primary tissues from 18 patients demonstrated protein expression of nAChR alpha1 and beta1 subunits, but not alpha7 subunit, in lung tumors, indicating preferential expression of the muscle-type receptor. In addition, the beta1 subunit showed significantly increased expression in lung tumors as compared to non-tumor bronchial tissue. The alpha1 subunit also showed evidence of high expression in lung tumors. Nicotine at a concentration of 10 microM caused phosphorylation of mitogen-activated protein kinase (MAPK) (p44/42) that could be inhibited using nAChR antagonists. Inhibition was observed at 100 nM alpha-bungarotoxin (alpha-BTX) or 10 microM hexamethonium (HEX); maximal inhibition was achieved using a combination of alpha-BTX and HEX. Akt was also phosphorylated in NSCLC cells after exposure to nicotine; this effect was inhibited by the PI3K inhibitor LY294002 and antagonists to the neuronal-type nAChR, but not to the muscle-type receptor. Nicotine triggered influx of calcium in the 273T NSCLC cell line, suggesting that L-type calcium channels were activated. 273T cells also showed greater activation of p44/42 MAPK than of Akt in response to nicotine. Cultures treated with nicotine and the EGFR tyrosine kinase inhibitor gefitinib showed a significant increase in the number of surviving cells compared to gefitinib alone. These data indicate that the muscle-type nAChR, rather than the alpha7 type, is highly expressed in NSCLC and leads to downstream activation of the p44/42 MAPK pathway. Neuronal-type receptors are also present and functional, as evidenced by antagonist studies, although, the expression levels are lower than muscle-type nAChR. They also lead to downstream activation of MAPK and Akt. Nicotine may play a role in regulating survival of NSCLC cells and endogenous acetylcholine released locally in the lung and/or chronic nicotine exposure might play a role in NSCLC development. In addition, exposure of NSCLC patients to nicotine through use of nicotine replacement products or use of tobacco products may alter the efficacy of therapy with EGFR inhibitors.

Acetylcholine↗
PubMed2006

Nicotine downregulates the l-selectin system that mediates cytotrophoblast emigration from cell columns and attachment to the uterine wall.

Here we show that maternal smoking downregulated, in a dose-dependent manner, cytotrophoblast expression of l-selectin and its TRA-1-81-reactive carbohydrate ligands. Cell islands -- cell columns that fail to make uterine attachments, often more numerous in the placentas of smokers -- exhibited an even greater downregulation of the l-selectin adhesion system. These effects were attributable to nicotine, since exposure of explanted villi to this drug in vitro reproduced the effects observed in situ. Videomicroscopy showed that the downstream consequences included inhibition of all stages of cytotrophoblast outgrowth from columns, including rolling adhesion within columns and generation of invasive cells at the distal ends. These results suggest that nicotine, acting through the l-selectin adhesion system, impairs the development of cell columns that connect the fetal portion of the placenta to the uterus, one possible reason why women who smoke have a much harder time achieving and sustaining pregnancy than their nonsmoking counterparts.

Antibodies, Monoclonal↗
PubMed2005

Light smoking and dependence symptoms in high-school students.

In high-school students, prevalence of smoking is high but few studies analyzed smoking in the student population according to nicotine content of smoked cigarettes and gender. We analyzed the responses to a questionnaire, including the modified Fagerström Tolerance Questionnaire (FTQ), administered to 555 students (382 males, 173 females) of a professional high school in Palermo, Italy, to assess the prevalence in both genders of: (1) smoking "light" and high nicotine (HN) cigarettes; (2) signs of nicotine dependence and (3) respiratory symptoms. Nicotine content of habitually smoked cigarettes was considered as "light" if 0.8 mg; as high if >0.8 mg. Forty-four percent of students smoked, without differences between genders. Two-thirds of the total sample reported "light" cigarette smoking (76.7% of females vs. 62.0% of males, P<0.05). On average, "light" cigarette smoking was associated with lower pack/year and FTQ global score compared to HN smoking. However, when FTQ global score was analyzed by taking into account pack/year, no major difference was found between "light" and HN cigarette smokers. Cough with phlegm and breathlessness were more frequently reported by smoking than non-smoking students, without differences between "light" and HN cigarette smokers. About 50% of smoking students reported having tried to quit, while only 3.4% of students were ex-smokers. "Light" smoking was common in high school students, especially among females. Dependence appeared more influenced by the smoking history than by nicotine content. Respiratory symptoms were similar in "light" and HN cigarette smokers.

Adolescent↗
PubMed2006

Cognitive effects of adjunctive 24-weeks Rivastigmine treatment to antipsychotics in schizophrenia: a randomized, placebo-controlled, double-blind investigation.

Cognitive impairment has the greatest impact on illness outcome in schizophrenia. The most significant challenge in schizophrenia therapeutics, thus, is to develop an efficacious treatment for cognitive impairments. Acetylcholinesterase inhibitors, such as Physostigmine and Rivastigmine, are considered effective treatments for cognitive decline in Alzheimer's Disease, where the loss of cholinergic neurons is thought to be responsible for various cognitive deficits. The current study investigated the cognitive effects of Rivastigmine given as an add-on therapy to antipsychotic-treated schizophrenia patients in a placebo-controlled double-blind design. The study initially involved 40 patients, of which 21 patients (11 assigned to Rivastigmine and 10 assigned to placebo) agreed to continued participation, remained on the study drug, and underwent assessment of executive functioning, verbal skills, verbal and spatial working memory, attention and psychomotor speed on three occasions: (i) at baseline, and then (ii) after 12 weeks and (iii) 24 weeks of treatment with placebo or Rivastigmine. The results failed to reveal significant improvement on any cognitive measure with Rivastigmine treatment, compared with the placebo treatment. Some cognitive variables showed significant practice effects in both the placebo and Rivastigmine groups. No effects were noted in symptoms or side effects ratings. The beneficial cognitive effects of Rivastigmine seen in an open-label preliminary study are not substantiated by this study. Future studies should investigate the effects of other procholinergic drugs, such as Galantamine, which also act on the nicotine receptors and may produce stronger cognitive effects in schizophrenia.

Adult↗
PubMed2006

Sleep effects of a 24-h versus a 16-h nicotine patch: a polysomnographic study during smoking cessation.

BACKGROUND AND PURPOSE: Sleep disturbance is a common symptom of tobacco withdrawal and might contribute to early relapse vulnerability in abstinent smokers. This study was designed to compare the effects on sleep of nicotine patches applied either for 24 h (Nicopatch) or 16 h (Nicorette). PATIENTS AND METHODS: During a short smoking cessation period (48 h), this open-label, randomised, two-period crossover study compared the effects on sleep of the two nicotine patches in 20 heavy smokers (9 women, 11 men). During each period, polysomnographic recordings were performed from 12 pm to 7 am for two consecutive nights (baseline and treatment nights). Smoking cessation started from 8 pm the day of the baseline sleep recordings, and treatments were applied around 8 am the following morning. RESULTS: Compared to the 16-h nicotine patch, smokers who received the 24-h nicotine patch experienced significantly less microarousals, a greater proportion of slow wave sleep, a higher REM density and higher rapid eye movement (REM) beta activities. CONCLUSIONS: The results of this study suggest that a 24-h nicotine patch is more efficient than a 16-h nicotine patch to alleviate tobacco withdrawal-induced sleep disturbances.

Administration, Cutaneous↗
PubMed2004

Oxidative mechanisms contributing to the developmental neurotoxicity of nicotine and chlorpyrifos.

Nicotine and chlorpyrifos are developmental neurotoxicants that, despite their differences in structure and mechanism of action, share many aspects for damage to the developing brain. Both are thought to generate oxidative radicals; in the current study, we evaluated their ability to produce lipid peroxidation in two in vitro models of neural cell development (PC12 and SH-SY5Y cells) and for nicotine, with treatment of adolescent rats in vivo. Nicotine and chlorpyrifos, in concentrations relevant to human exposures, elicited an increase in thiobarbituric-acid-reactive species (TBARS) in undifferentiated cells, an effect that was prevented by addition of the antioxidant, Vitamin E. Initiating differentiation with nerve growth factor, which enhances nicotinic acetylcholine receptor expression, increased the TBARS response to nicotine but not chlorpyrifos, suggesting that the two agents act by different originating mechanisms to converge on the endpoint of oxidative damage. Furthermore, nicotine protected the cells from oxidative damage evoked by chlorpyrifos and similarly blocked the antimitotic effect of chlorpyrifos. Treatment of adolescent rats with nicotine elicited increases in TBARS in multiple brain regions when given in doses that simulate plasma nicotine concentrations found in smokers or at one-tenth the dose. Our results indicate that nicotine and chlorpyrifos elicit oxidative damage to developing neural cells both in vitro and in vivo, a mechanism that explains some of the neurodevelopmental endpoints that are common to the two agents. The balance between neuroprotectant and neurotoxicant actions of nicotine may be particularly important in situations where exposure to tobacco smoke is combined with other prooxidant insults.

Animals↗
PubMed2005

Limited modulation of the transport activity of the human multidrug resistance proteins MRP1, MRP2 and MRP3 by nicotine glucuronide metabolites.

The human ATP-binding cassette proteins MRP1 (ABCC1), MRP2 (ABCC2) and MRP3 (ABCC3) are active transporters of antineoplastic drugs as well as conjugated metabolites and other organic anions. In addition to being substrates, many glucuronide, glutathione and sulfate conjugates can also inhibit the transport activities of these MRP-related proteins, sometimes in a glutathione (GSH)-dependent manner. Nicotine is the major addictive component of cigarette smoke. Three glucuronide metabolites of this compound have been identified in vivo: nicotine-N-glucuronide, cotinine-N-glucuronide and trans-hydroxycotinine-O-glucuronide. In this study, we first chemically synthesized trans-hydroxycotinine-O-glucuronide and then tested the ability of this compound, nicotine-N-glucuronide and cotinine-N-glucuronide to modulate the vesicular transport of several organic anions by MRP1, MRP2 and MRP3. We observed that none of the three metabolites at concentrations up to 100muM significantly affected organic anion transport by MRP1 or MRP2, either in the absence or presence of GSH. MRP3-mediated transport of 17beta-estradiol 17-(beta-d-glucuronide) and methotrexate were partially inhibited by trans-hydroxycotinine-O-glucuronide (300 microM) (by 70% and 50%, respectively), whereas nicotine-N-glucuronide and cotinine-N-glucuronide had no effect. We conclude that the physiological functions of MRP1, MRP2 and MRP3 are not likely to be substantially affected by nicotine glucuronide metabolites at concentrations achievable in human serum.

ATP-Binding Cassette Transporters↗
PubMed2006

Positive visual phenomena in space: A scientific case and a safety issue in space travel.

Most astronauts on Apollo, Skylab, and MIR reported 'flashes of light' occurring in different shapes and apparently moving across the visual field, in the absence of auditory, somatosensory, or olfactory abnormal percepts. A temporal correlation with heavy nuclei or protons has been documented in space and comparable phosphenes were observed by volunteers whose eyes were exposed to accelerated heavy ions at intensities below the threshold for Cerenkov visible radiation. An interaction between heavy ions and the retina was suggested. However, the biophysics of heavy ions or protons action remains undefined, the effects on photoreceptors and neuroretina have not been differentiated, and some direct action on the visual cortex never ruled out. Phosphenes are common in migraine and are known to occur also in response to the electrical stimulation of ganglion cells (in retinas without photoreceptors), optic pathways or visual cortex, with mechanisms that bypass the chemically gated channels. Intrinsic photosensitive ganglion cells exist in the retina of teleost fish and mammals. In the hypothesis of a peculiar sensitivity to subatomic particles of the visual system, phosphenes due to the activation of processes by-passing the photoreceptors would raise questions about human safety in space. The issue is particularly relevant with experiments of increasing duration being now operative in the International Space Station (ISS) and with plans of space travel outside the geomagnetic shield. Research is in progress both in the ISS and on animal models, in the framework of the NASA/ESA actions to improve the astronauts' health in space.

Cosmic Radiation↗
PubMed2005

Smoke composition and predicting relationships for international commercial cigarettes smoked with three machine-smoking conditions.

The study objectives were to determine the effects of smoking machine puffing parameters on mainstream smoke composition and to express those effects as predicting relationships. Forty-eight commercial Philip Morris USA and Philip Morris International cigarettes from international markets and the 1R4F reference cigarette were machine-smoked using smoking conditions defined by the International Organization of Standardization (ISO), the Massachusetts Department of Public Health (MDPH), and Health Canada (HC). Cigarette tobacco fillers were analyzed for nitrate, nicotine, tobacco-specific nitrosamines (TSNA), and ammonia. Mainstream yields for tar and 44 individual smoke constituents and "smoke pH" were determined. Cigarette constituent yields typically increased in the order ISO<MDPH<HC. Relative yield increases were generally greater for cigarettes with higher initial filter ventilation and were also generally greater for vapor-phase constituents than for particulate-phase constituents. Predicting relationships were developed between ISO tar and ISO, MDPH, and HC constituent yields and between MDPH tar and HC tar and respective smoking condition yields. MDPH and HC constituent yields could be predicted with similar reliability using ISO tar or the corresponding smoking-condition tar. The reliability of the relationships varied from strong to weak, depending on particular constituents. Weak predicting relationships for nitrogen oxides and TSNA's, for example, were improved with inclusion of tobacco filler composition factors. "Smoke pH" was similar for all cigarettes at any one smoking condition, and overall marginally lower at HC conditions than at ISO or MDPH conditions.

Ammonia↗
PubMed1996

Effect of 21 mg transdermal nicotine patches and smoking cessation on heart rate variability.

The effect of smoking cessation on cardiac autonomic tone, as reflected by indexes of heart rate variability (HRV), has not been reported. Current smokers (n = 54, mean +/- SD age 43 +/- 12 years) who desired to quit, and were smoking > or = 1 pack/day and had made > or = 1 prior attempt at quitting, had 24-hour electrocardiographic recordings. They then attended smoking cessation classes and used transdermal nicotine patches while abstaining from smoking. After 4 to 6 weeks of using 21 mg patches, the 24-hour electrocardiogram was repeated (n = 35). Four weeks after cessation of patch use, the 24-hour electrocardiogram was again recorded in subjects who continued to be abstinent (n = 25). Time and frequency domain measures of HRV based on normal R to R (NN) intervals were computed for all recordings. Smoking cessation significantly decreased heart rate, and increased all 24-hour time and frequency domain indexes of HRV. Part of this change occurred in the transition from smoking to the patch, and further changes occurred with cessation of patch use. For example, the standard deviation of average NN intervals was 114 +/- 28 ms at baseline, 121 +/- 41 ms with the patch, and 135 +/- 26 ms after quitting. At 4 weeks after cessation of all nicotine use, the average heart rate remained higher, and HRV remained lower than values reported for healthy, middle-aged adults.

Administration, Cutaneous↗
PubMed2000

Nicotine attenuates arachidonic acid-induced neurotoxicity in cultured spinal cord neurons.

Arachidonic acid release from cellular membranes due to spinal cord trauma may be one of the principal destructive events that can lead to progressive injury to spinal cord tissue. Exposure to arachidonic acid can compromise neuronal survival and viability. Because nicotine is known to be a neuroprotective agent, we propose that it can prevent arachidonic acid-induced neurotoxicity. To study this hypothesis, effects of nicotine on mitochondrial function, cellular energy content and apoptotic cell death were measured in cultured spinal cord neurons treated with arachidonic acid. Nicotine attenuated arachidonic acid-induced compromised cell viability and cellular ATP levels in spinal cord neurons. Nicotine exerted these protective effects when used at the concentration of 10 microM and only after a 2-h pre-treatment before a co-exposure to arachidonic acid. Antagonists of nicotinic receptors, such as alpha-bungarotoxin or mecamylamine, only partially reversed these neuroprotective effects of nicotine. In addition, nicotine prevented arachidonic acid-induced activation of caspase-3 activity and apoptotic cell death. These results indicate that nicotine pre-treatment can exert a protective effect against arachidonic acid-induced injury to spinal cord neurons.

Adenosine Triphosphate↗
PubMed2000

Nicotine-induced locomotor activity is increased by preexposure of rats to prenatal stress.

Genetic factors are believed to play a predominant role in the individual differences observed in behavioral and pharmacological responses to drugs of abuse. An increasing literature indicates, however, that epigenetic factors can be involved as well. In this report we examined whether developmental changes induced by prenatal stress could alter the way animals respond to the psychostimulant effect of nicotine when adults. The results show that nicotine induces a dose-dependent increase of locomotor activity in both groups, and that prenatally-stressed animals exhibit a higher behavioral response at all doses. This study emphasizes the importance of early environment in the later development of drug-related behavior.

Animals↗
PubMed2002

Effects of extrinsic autonomic inputs on expression of c-Fos immunoreactivity in myenteric neurons of the guinea pig distal colon.

c-Fos protein is a nuclear protein coded by c-fos proto-oncogene subsequent to synaptic activation of the neurons. We used immunohistochemical methods to visualize the expression of c-Fos protein in myenteric neurons of the guinea pig distal colon and examined the effects of the extrinsic autonomic inputs on the enteric circuits. No c-Fos immunoreactivity was observed in the colonic segments fixed immediately after removal from the animal body. A number of c-Fos-immunoreactive nuclei of myenteric neurons, however, appeared in all preparations that were incubated in Krebs solution in vitro (n=10). Application of tetrodotoxin (0.2 microM) abolished the expression of c-Fos-immunoreactivity (n=6), but hexamethonium (100 microM) failed to decrease the number of c-Fos-positive neurons despite a complete suppression of spontaneous peristaltic movements (n=5). Neither the electrical stimulation (n=8) nor the severing of the pelvic nerves (n=5) changed the number of c-Fos-positive neurons. Application of clonidine, an alpha(2)-agonist, (0.1 microM) abolished the expression of c-Fos protein in all preparations (n=5), while denervation of the sympathetic fibers in the lumbar colonic and hypogastric nerves in vivo increased the number of c-Fos-positive neurons (n=5). The results indicate that the enteric circuit in the distal part of the gastrointestinal tract is under tonic inhibition by the sympathetic nervous system from the lumbar spinal cord. c-Fos immunoreactivity expressed in the colonic preparations in vivo might be the results of enhanced activation of non-nicotinic receptors after removal of the sympathetic inhibition.

Adrenergic alpha-Agonists↗