Stimulatory Effect Of Nicotine Research Articles

Inhalation of electronic cigarette aerosol induces reflex bronchoconstriction by activation of vagal bronchopulmonary C-fibers.

The electronic cigarette (e-cig) has been suggested as a safer alternative to tobacco cigarettes. However, the health effects of e-cigs on the airways have not been fully investigated. Nicotine, the primary chemical constituent of the e-cig aerosol, has been shown to stimulate vagal bronchopulmonary C-fiber sensory nerves, which upon activation can elicit vigorous pulmonary defense reflexes, including airway constriction. In this study, we investigated the bronchomotor response to e-cig inhalation challenge in anesthetized guinea pigs and the mechanisms involved in regulating these responses. Our results showed that delivery of a single puff of e-cig aerosol into the lung triggered immediately a transient bronchoconstriction that sustained for >2 min. The increase in airway resistance was almost completely abolished by a pretreatment with either intravenous injection of atropine or inhalation of aerosolized lidocaine, suggesting that the bronchoconstriction was elicited by cholinergic reflex mechanism and stimulation of airway sensory nerves was probably involved. Indeed, electrophysiological recording further confirmed that inhalation of e-cig aerosol exerted a pronounced stimulatory effect on vagal bronchopulmonary C-fibers. These effects on airway resistance and bronchopulmonary C-fiber activity were absent when the e-cig aerosol containing zero nicotine was inhaled, indicating a critical role of nicotine. Furthermore, a pretreatment with nicotinic acetylcholine receptor antagonists by inhalation completely prevented the airway constriction evoked by e-cig aerosol inhalation. In conclusion, inhalation of a single puff of e-cig aerosol caused a transient bronchoconstriction that was mediated through cholinergic reflex and triggered by a stimulatory effect of nicotine on vagal bronchopulmonary C-fiber afferents.

Effect of nicotine from tobacco root exudates on chemotaxis, growth, biocontrol efficiency, and colonization by Pseudomonasaeruginosa NXHG29.

Accumulated evidence suggests that root exudates have a major role in mediating plant-microbe interactions in the rhizosphere. Here, we characterized tobaccorootexudates (TREs) by GC-MS and nicotine, scopoletin, and octadecane were identified as three main components of TREs. Qualitative andquantitative chemotaxis assays revealed that Pseudomonas aeruginosa NXHG29 with antagonistic activity displayed positive chemotactic responses towards TREs and their three main components (nicotine, scopoletin, octadecane) and its enhanced chemotaxis were induced by these substances in a concentration-dependent manner. Furthermore, following GC-MS and chemotaxis analysis, nicotine was selected as the target for evaluation of the effect on NXHG29 regarding antagonism, growth, root colonization and biocontrol efficiency. Results of in vitro studies showed that nicotine as a sole carbon source could enhance growth of NXHG29 and significantly increased the antagonism of NXHG29. We also demonstrated that nicotine exerted enhancing effects on the colonization ability of NXHG29 on tobacco roots by combining CLSM observations with investigation of population leveldynamics by selective dilution plating method. Results from greenhouse experiments suggested nicotine exhibited stimulatory effects on the biocontrol efficiency of NXHG29 against bacterial wilt and black shank on tobacco. The stimulatory effect of nicotine was affected by the concentration and timing of nicotine application and further supported by the results of population level of NXHG29 on tobacco roots. This is the first report on the enhancement effect of nicotine from TREs on an antagonistic bacterium for its root colonization, control of soil-borne pathogens, regarding the chemotaxis and in vitro antagonism and growth.

Nicotine stimulates collagen type I expression in lung via \u03b17 nicotinic acetylcholine receptors

BackgroundTobacco-related chronic lung diseases are characterized by alterations in lung architecture leading to decreased lung function. Knowledge of the exact mechanisms involved in tobacco-induced tissue remodeling and inflammation remains incomplete. We hypothesize that nicotine stimulates the expression of extracellular matrix proteins, leading to relative changes in lung matrix composition, which may affect immune cells entering the lung after injury.MethodsPulmonary fibroblasts from wildtype and α7 nicotinic acetylcholine receptor knockout (α7KO) mice were exposed to nicotine and examined for collagen type 1 mRNA and protein expression. Testing the potential role on immune cell function, pulmonary fibroblasts were retained in culture for 120 h. The fibroblasts were eliminated by osmotic lysis and the remaining matrix-coated dishes were washed thoroughly. U937 cells were incubated on the matrix-coated dishes for 24 h followed by evaluation of IL-1β gene expression. Wildtype or α7KO C57BL/6 mice (female, 8–12 weeks) were fed normal diet and exposed to nicotine in their drinking water (100 μg/ml) for 8-12weeks. Lungs were processed for mRNA, protein, and histology. Statistical significance was determined at p ≤ .05 by two-tailed test or 2-way ANOVA with Bonferroni posttest.ResultsWe found that nicotine stimulated collagen type I mRNA and protein expression in a dose-dependent manner and up to 72 h in primary lung fibroblasts. The stimulatory effect of nicotine was inhibited in α7KO primary lung fibroblasts. Testing the potential role of these events on immune cell function, U937 monocytic cells were cultured atop matrices derived from nicotine-treated lung fibroblasts. These cells expressed more IL-1β than those cultured atop matrices derived from untreated fibroblasts, and antibodies against the α2β1 collagen integrin receptor inhibited the effect. Nicotine also stimulated fibroblast proliferation via MEK-1/ERK, unveiling a potentially amplifying pathway. In vivo, nicotine increased collagen type I expression was detected in wildtype, but not in α7KO mice. Wildtype mice showed increased collagen staining in lung, primarily around the airways.ConclusionsThese observations suggest that nicotine stimulates fibroblast proliferation and their expression of collagen type I through α7 nAChRs, thereby altering the relative composition of the lung matrix without impacting the overall lung architecture; this may influence inflammatory responses after injury.

Differential behavioral effects of nicotine in adult male and female rats with a history of prenatal methamphetamine exposure

The goal of the current study was to assess the effects of prenatal methamphetamine (MA)/saline exposure on nicotine-induced stimulant and aversive effects in both male and female adult rats. The aversive effects of nicotine were assessed using the nicotine-induced conditioned taste aversion model (0.4mg/kg, base), while the stimulant effects of nicotine were measured by assessing changes in spontaneous locomotor activity after subcutaneous administration of different doses of nicotine (0, 0.1 & 0.4mg/kg, base). The aversive effects of nicotine were significantly decreased in male, but not in female rats with a history of prenatal MA exposure compared to respective saline controls. No influence of prenatal MA exposure was observed on nicotine-induced increase in locomotor activity in either male or female rats. In conclusion, males with a history of prenatal MA exposure may be more vulnerable to nicotine addiction due to a decrease in nicotine-induced aversive effects.

Nicotine stimulation increases proliferation and matrix metalloproteinases-2 and -28 expression in human dental pulp cells.

Dental pulp is the specialized tissue responsible for maintaining tooth viability. When tooth mineralized matrix is damaged, pulp is exposed to a plethora of environmental stimuli. In particular, in smokers, pulp become exposed to very high concentrations of nicotine. The aim of this study was to investigate the effect of direct nicotine stimulation on human dental pulp cell proliferation. Moreover, as it is known that nicotine could upregulate the expression of matrix metalloproteinases (MMPs), enzymes involved in pulpal inflammation, the effects of nicotine stimulation on MMP-2 and MMP-28 gene expression have also been investigated. Human dental pulp cells were extracted from impacted third molars obtained from healthy patients undergoing routine orthodontic treatments. Such cells were treated with growing concentrations of nicotine in the presence or absence of a nicotine antagonist (hexamethonium chloride) or of a MEK signaling inhibitor (PD98059). Cell proliferation was evaluated by cell counting, while nicotine effects on MMP expression were evaluated by PCR. The data obtained indicate that nicotine is able to increase human dental pulp cell proliferation by acting through nicotinic cholinergic receptors and downstream MAPK signaling pathway. Moreover, it is also able to increase both MMP-2 and MMP-28 gene expression. In summary these results highlight that direct exposure of human dental pulp cells to nicotine results in an inflammatory response, that could have a role in pulpal inflammation onset, a pathological condition that, when ignored, could eventually spread to the surrounding alveolar bone and progress to pulp necrosis.

Regulatory effect of nicotine on collagen-induced arthritis and on the induction and function of in vitro-cultured Th17 cells

Objectives. To determine the effect of nicotine stimulation on collagen-induced arthritis (CIA), especially on Th17 cells, and the influence of activated acetylcholine receptor signaling on the induction and function of in vitro-cultured Th17 cells.Methods. Mice were divided into control and experimental (nicotine) group, and PBS or nicotine-PBS was orally administered from Day 21 to Day 28. Phenotypic changes in spleen CD4+ cells were measured by flow cytometry. α7nAChR expression in Th17 cells was detected using flow cytometry, western blotting and real-time PCR. Purified Th17 cells were further stimulated with nicotine. The cytometric bead array (CBA) assay was employed to measure TNF-α levels in mice serum and IL-17A levels in the supernatants of nicotine-treated cell cultures.Results. Compared with their counterparts, mice receiving oral nicotine showed a delayed progress of arthritis and more attenuated signs of histological changes. Moreover, serum TNFα levels were lower in the nicotine-treated group. Spleen IL-17 level of nicotine-treated mice was lower than that of the control group, and the mRNA expression of pro-inflammatory cytokines (IL-17A and IL-6) in splenocytes were also lower than that of the control group. α7nAChR expression was detected on in vitro-cultured IL-17A+ cells. Cells treated with 10 − 6 M nicotine expressed lower IL-17A levels. Similarly, supernatants from nicotine-treated cell cultures also showed lower IL-17A levels.Conclusions. Nicotine stimulation attenuated signs and severity of arthritis in mice. Activation of nicotine acetylcholine receptors on in vitro-cultured Th17 cells decreased their pro-inflammatory function, which may play a potential role in alleviating arthritis in mice.

Investigation of Psen1&2 Genes in Early Onset Alzheimer’s Disease Patients

Investigation of Psen1&2 Genes in Early Onset Alzheimer’s Disease Patients

Effects of nicotine stimulation on spikes, theta frequency oscillations, and spike-theta oscillation relationship in rat medial septum diagonal band Broca slices

Spiking activities and neuronal network oscillations in the theta frequency range have been found in many cortical areas during information processing. The aim of this study is to determine whether nicotinic acetylcholine receptors (nAChRs) mediate neuronal network activity in rat medial septum diagonal band Broca (MSDB) slices. Extracellular field potentials were recorded in the slices using an Axoprobe 1A amplifier. Data analysis was performed off-line. Spike sorting and local field potential (LFP) analyses were performed using Spike2 software. The role of spiking activity in the generation of LFP oscillations in the slices was determined by analyzing the phase-time relationship between the spikes and LFP oscillations. Circular statistic analysis based on the Rayleigh test was used to determine the significance of phase relationships between the spikes and LFP oscillations. The timing relationship was examined by quantifying the spike-field coherence (SFC). Application of nicotine (250 nmol/L) induced prominent LFP oscillations in the theta frequency band and both small- and large-amplitude population spiking activity in the slices. These spikes were phase-locked to theta oscillations at specific phases. The Rayleigh test showed a statistically significant relationship in phase-locking between the spikes and theta oscillations. Larger changes in the SFC were observed for large-amplitude spikes, indicating an accurate timing relationship between this type of spike and LFP oscillations. The nicotine-induced spiking activity (large-amplitude population spikes) was suppressed by the nAChR antagonist dihydro-β-erythroidine (0.3 μmol/L). The results demonstrate that large-amplitude spikes are phase-locked to theta oscillations and have a high spike-timing accuracy, which are likely a main contributor to the theta oscillations generated in MSDB during nicotine receptor activation.

Influence of CPAP treatment on inflammation in patients with obstructive sleep apnea: Is it a matter of time or a matter of marker?

It was with a great interest that we have read the article entitled “Effect of CPAP treatment on endothelial function and plasma CRP levels in patients with sleep apnea” by Athanasios Panoutsopoulos et al. published recently in this journal [1]. After reading the article, we benefited a lot from it. In recent years our department has been studying the relationship between inflammation, coronary heart disease and sleep apnea. Athanasios Panoutsopoulos and coworkers encouraged us greatly. We would like to share our opinions about the study. The study demonstrated that Continuous positive airway pressure (CPAP) treatment had a relevant upon systemic and local inflammation and provided new insight into pathophysiological pathways of obstructive sleep apnea syndrome (OSAS). OSAS was widely accepted as a cardiovascular risk factor. The close association of OSAS and conventional cardiovascular risk factors including hypertension, diabetes mellitus, dyslipidemia and obesity added to the adverse cardiovascular complication. Studies have suggested a strong bidirectional association between OSAS and metabolic syndrome (MS). Inflammation was believed to play a role in the pathogenesis of cardiovascular disease. OSAS was closely associated with inflammation, but obesity may be a confounding factor. Obesity has emerged as one of the most prevalent diseases in the world. The mechanisms leading to obesity-related morbidities were likely multifactorial, and absolutely included activation of inflammatory pathways. Both obesity and OSAS could modulate the expression and secretion of systemic and airway inflammatory cytokines. So, we should pay certain attention to the change of weight. CPAP was effective in the treatment of OSAS, but adherence was a major barrier. The subjects completed the CPAP treatment with good adherence in this study. Several studies reported that CPAP treatment could reverse pathophysiological changes, reduce the risk of cardiovascular events and mortality in subjects with OSAS. C-reactive protein (CRP) was a prototypic marker of inflammation that has repeatedly shown promise as a potentially reliable biomarker of cardiovascular morbidity. Hypertension induced by OSAS may be multifactorial in origin, and systemic inflammation was one of the major factors. OSAS patients with hypertension have higher level of inflammation and insulin resistance. Sleep apnea was common in patients with coronary artery disease (CAD). Inflammatory processes played an important role in the pathogenesis of atherosclerosis. Inflammation may be linked to CAD progression by accelerating atherosclerotic processes. Statins has been widely utilized to reduce cardiovascular risk in patients with cardiovascular disease. The benefit has been attributed both to cholesterol lowering and “anti-inflammatory” effects. Smoking was a known risk factor and was reported to be associated with an increased prevalence of OSAS. Due to the smoking-induced upper airway inflammation and stimulant effects of nicotine on upper airway, smoking may participate in the pathophysiology of OSA. Some studies confirmed that physical exercise could improve excessive daytime sleepiness due to its improvement in inflammatory profiles.

Gamma-Amino Butyric Acid Inhibits the Nicotine-Imposed Stimulatory Challenge in Xenograft Models of Non-Small Cell Lung Carcinoma

Non-small cell lung carcinoma (NSCLC) is the leading type of lung cancer; smoking is a documented risk factor. Nicotinic acetylcholine receptor (nAChR)-mediated intracellular signaling in response to nicotine has recently been implicated in the growth regulation of NSCLC. In the current study nude mice carrying xenografts of the human lung NSCLC cell lines NCI-H322 or NCI-H441 were used as animal models. Nicotine administration and gamma aminobutyric acid (GABA) treatment lasted for 30 days. Catecholamines, cortisol, GABA, and cAMP were analyzed in blood and tumor tissues by immunoassays. Expression of nicotinic receptors and effector proteins in the xenografts was assessed by Western blotting. Our data indicate that nicotine stimulated the growth of NSCLC xenografts via modulation of nAChR upregulation and activation of cAMP signaling. The nicotine-treated group showed an enhanced level of stress neurotransmitters and second messenger cAMP in serum, blood cellular fraction, and xenograft tissues. Activation of critical proteins in the oncogenic pathway, including CREB, ERK, Akt, and Src, and upregulation of α-4 and α-7 subunits of nAChR provided mechanistic insight for the observed stimulatory effect of nicotine. Interestingly, GABA, being an antagonist to cAMP signaling, showed a promising intervention by reversing the stimulatory effect of nicotine on cancer growth and all signaling pathways. GABA has potential to lower the risk of NSCLC among smokers and could be used to enhance the clinical outcome of standard cancer intervention strategies.

New Approaches to Identifying Rare Genetic Variants Associated with Nicotine Dependence

f p t f a l T he publication of candidate gene studies related to nicotine dependence (ND) increased rapidly in the late 1990s and 2000s with a number of studies supporting a role for variation n nicotinic acetycholine receptor (nAchR) genes. For example, sevral studies reported that variation in the CHRNA4 gene was related o the stimulatory effects of nicotine and nicotine dependence as ell as to treatment outcomes (1,2). The CHRNA4 gene codes for the 4 subunit of the 4/ 2 receptor. The 4/ 2 is the most common AchR in the brain and arguably the most studied nAchR with espect to ND. Other notable candidate gene findings include studes that reported an association between smoking and variations in ther nAchR subunit genes, such as CHRNA5 and CHRNA3 (3). Thus, andidate gene studies have suggested that variation in the genes oding for subunits of nAchRs may play an important role in ND tiology and treatment response. Within the last 5 years, there was a shift from an emphasis on andidate gene studies to an emphasis on genome-wide associaion studies (GWAS). One of the largest genome-wide analyses nvolved an analysis of 41,150 smokers (4). These analyses identified hree loci that were significantly associated with smoking. Two of he three loci were previously identified in candidate gene studies, s noted above (3). Although confirmatory evidence regarding the ole of nAchR genes is valuable and although genome-wide aproaches have led to the identification of new genetic associations, thers have noted some important limitations of the genome-wide pproach. For example, it has been questioned why genome-wide tudies with large sample sizes have identified genes that at best xplain only 1-2% of the genetic variance in a phenotype. Although here has been some debate about the reasons, explanations inlude the ideas that GWAS do not adequately capture the effect of are mutations, that they do not include neurobiological phenoypes, and that they rely heavily on statistical approaches that demphasize biological plausibility (5). In response to these limitations, the field is now turning to the se of next-generation sequencing, made possible by recent techological developments that have greatly reduced the costs of equencing, to identify and evaluate the role of rare mutations. In ddition, scientists are including neurobiological phenotypes that ore directly capture the putative underlying molecular effects of a iven genetic variant and phenotypes that are mechanistically reated to the disorder of interest. In this issue of Biological Psychiatry, ie et al. (6) report findings from a study of rare variants in the CHRNA4 gene and ND that utilizes both sequencing and neurobiological phenotypes, which allows for the identification of rare variants and addresses the biological function of these variants. The authors sequenced exon 5 of the CHRNA4 gene in 1000 nicotine-dependent cases and 1000 controls and identified 169 rare

Abstract 2948: Nicotine-induced expression of MUC4 in pancreatic cancer cells is mediated by E2F1 and STAT-1 upregulation: Relevance to smoking and pancreatic cancer

Abstract The membrane-bound mucins belong to an ever-increasing family of O-glycoproteins. Based on their structure and localization at the cell surface they are thought to play important biological roles in cell-cell and cell-matrix interactions and cell signaling. The human mucin gene MUC4 is overexpressed in pancreatic cancer and cancer cell lines, while remaining undetectable in the normal pancreas, indicating its potential role in pancreatic cancer pathogenesis. Smoking has been correlated with pancreatic cancer, even though the underlying molecular mechanisms are unknown. Attempts were made to elucidate the molecular mechanisms involved in the regulation of MUC4 gene expression by nicotine as well as cytokines. In this report, we used pancreatic cancer cell lines CD18 as well as PANC1 stimulated with nicotine to identify the signaling pathways and transcription factors regulating MUC4 expression. Through chromatin immunoprecipiation assay and real-time PCR, we found that transcription factors E2F1 and STAT1 can positively regulate MUC4 expression. Additionally, the effect is abrogated by short interfering RNA (siRNA)-mediated inhibition of E2F1 and STAT-1 expression, supporting pivotal role played by E2F1 and STAT-1 in MUC4 regulation. The same molecules were responsible for MUC4 induction by nicotine in combination with IFN- and RA. Inhibiting the acetylacholinergic receptors with inhibitors reversed the effects of nicotine stimulation. Similarly, the induction was dependent on the PI3 kinase as well as Src signaling pathways. Additionally, nicotine treatment alone and in combination with IFN- and RA activates and relocalizes signal transducer and activator of transcription-1 (STAT-1) via phosphorylating Jak2 at the tyrosine residue to induce MUC4. These results suggest that nicotine alone and also in combination with IFN- and RA, upregulates the MUC4 expression involving JAK-STAT pathway. In conclusion, our findings identify novel mechanisms for MUC4 regulation in pancreatic cancer cells and will be helpful understanding the transcriptional regulation of MUC4 in response to exposure to nicotine and tobacco smoke. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2948.

Tobacco smoking produces widespread dominant brain wave alpha frequency increases

The major pharmacological ingredient in tobacco smoke is nicotine, a mild stimulant known to alter brain electrical activity. The objective of this study was to determine if tobacco smoking in humans produces localized or widespread neocortical dominant alpha electroencephalographic (EEG) frequency increases consistent with nicotine stimulation of the brainstem activating system in animals. Twenty-two male volunteer non-deprived tobacco smokers were studied. They were asked not to smoke for at least 1 h before the experiment in mid-morning as part of their usual smoking schedule. In the laboratory, they sham smoked and then smoked their favorite tobacco cigarette. Two experimental sessions (#1 and #2) were conducted, separated by a one to two month interval. In both sessions, there were minor statistically significant increases in the dominant alpha frequencies after sham smoking. In both sessions, after the subjects smoked a favorite tobacco cigarette there was a significant generalized increase in dominant alpha EEG frequencies in most scalp recording sites. This study demonstrates that tobacco smoking produces widespread bilateral neocortical increases in dominant alpha EEG frequencies consistent with the stimulant effects of nicotine on the brainstem reticular activating system.

Effects of nicotine and lipopolysaccharide on the expression of matrix metalloproteinases, plasminogen activators, and their inhibitors in human osteoblasts

Objective Lipopolysaccharide (LPS) from periodontopathic bacteria can initiate alveolar bone loss through the induction of host-derived cytokines. Smoking increases the risk and severity of periodontitis. We examined the effects of nicotine and LPS on the expression of matrix metalloproteinases (MMPs), plasminogen activators (PAs), and their inhibitors, including tissue inhibitors of metalloproteinases (TIMPs) and PA inhibitor-1 (PAI-1), in osteoblasts. Methods The cells were cultured with or without 10 −4 M nicotine and 100 ng/ml LPS for 12 days or with 100 μg/ml polymyxin B, 10 −4 M d-tubocurarine, 10 μmol/ml NS398, or 10 −6 M celecoxib in the presence of either nicotine or LPS for 12 days. The gene and protein expression levels for MMPs, PAs, TIMPs, and PAI-1 were examined using real-time PCR and ELISAs, respectively. PGE 2 production was determined using an ELISA. Results The addition of nicotine and/or LPS to the culture medium increased the expression of MMP-1, -2, and -3 and tissue-type PA (tPA); decreased the expression of TIMP-1, -3, and -4; and did not affect expression of TIMP-2 or PAI-1. In the presence of d-tubocurarine or polymyxin B, neither nicotine nor LPS stimulated the expression of MMP-1. In the presence of NS398 or celecoxib, the stimulatory effects of nicotine and LPS on MMP-1 expression were unchanged, but they were unable to stimulate PGE 2 production. Conclusion These results suggest that nicotine and LPS stimulate the resorption process that occurs during turnover of osteoid by increasing the production of MMPs and tPA and by decreasing the production of TIMPs. Furthermore, they suggest that the stimulatory effect of nicotine and LPS on PGE 2 production is independent of their stimulatory effect on MMP-1 expression.

Expression of neuronal nicotinic acetylcholine receptors in rat vagal pulmonary sensory neurons

It has been known that cigarette smoke inhalation causes airway irritation and cough, and the effect is primarily caused by a stimulatory effect of nicotine on bronchopulmonary sensory nerves. However, little is known about the expression of nicotinic acetylcholine receptors (nAChRs) in these afferents. In this study, whole‐cell patch‐clamp recording and RT‐PCR were carried out to examine the expression and function of nAChRs in isolated rat vagal pulmonary sensory neurons that were identified by retrograde labeling with a fluorescent tracer. Patch‐clamp recordings demonstrated that application of acetylcholine concentration‐dependently evoked an inward current in a subset of pulmonary sensory neurons, which was inhibited by hexamethonium. Application of nicotine or 1,1‐dimethyl‐4‐phenylpiperazinium (DMPP) also activated these neurons, evoking an inward current in voltage‐clamp configuration and causing depolarization and action potential in current‐clamp recordings. RT‐PCR analysis further demonstrated the expression of mRNA encoding for the nAChR subunits α4, α5, α6, α7, β2, β3 and β4, but not α2 and α3 in these neurons. In conclusion, our data have demonstrated the expression of neuronal nAChRs in rat vagal pulmonary sensory neurons. Supported by NIH HL067379 and Parker B. Francis Fellowship in Pulmonary Research.

The Neurobiological Bases for the Pharmacotherapy of Nicotine Addiction

Nicotine, the major psychoactive agent present in tobacco, acts as a potent addictive drug both in humans and laboratory animals, whose locomotor activity is also stimulated. A large body of evidence indicates that the locomotor activation and the reinforcing effects of nicotine may be related to its stimulatory effects on the mesolimbic dopaminergic function. Thus, it is now well established that nicotine can increase in vivo DA outflow in the nucleus accumbens and the corpus striatum. The stimulatory effect of nicotine on DA release most probably results from its ability to excite the neuronal firing rate and to increase the bursting activity of DA neurons in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA), and from its stimulatory action on DA terminals in the corpus striatum and the nucleus accumbens. The neurochemical data are consistent with neuroanatomical findings showing the presence of nicotinic acetylcholine receptors (nAChRs) in the SNc, the VTA, and in projection areas of the central dopaminergic system such as the corpus striatum and the nucleus accumbens. Several lines of evidence indicate that the reinforcing properties of drugs of abuse, including nicotine, can be affected by a number of transmitter systems which may act by modulating central dopaminergic function. In this paper, the neurobiological mechanisms underlying nicotine addiction will be reviewed, and the possible strategies for new pharmacological treatments of nicotine dependence will be examined.

Acute effects of cigarette smoking on multifocal electroretinogram

Cigarette smoking was shown to have stimulant effects on pattern visual-evoked potentials. The aim of this study was to investigate the acute effects of cigarette smoking on multifocal electroretinogram (mfERG). This prospective case-control study was held in a tertiary referral centre in Turkish Armed Forces. mfERGs were investigated in a group of habitual smokers (30 right eyes of 30 subjects) in separate real smoking and sham smoking sessions. mfERG responses of the subjects were recorded after overnight abstinence. The responses were averaged over five retinal regions, the central hexagon (CH; central 6 degrees) and four concentric rings (ring 1 [R1; 7-12 degrees], ring 2 [R2; 13-18 degrees], ring 3 [R3; 19-24 degrees], ring 4 [R4; 25-30 degrees]). On each session mfERGs were recorded before (BS) and after smoking (AS) conditions. Regarding P1 amplitudes (first positive deflection of the mfERG) in the real smoking sessions, the differences were significant in the CH (BS: 66.2 +/- 16.3 microV, AS: 73.3 +/- 19.6 microV, P < 0.001), in R1 (BS: 44.3 +/- 13.0, AS: 48.3 +/- 16.0, P = 0.004) and in R2 (BS: 30.1 +/- 8.3, AS: 33.7 +/- 9.7, P = 0.002). Similar results were found for N1 amplitudes and P1 and N1 (first negative deflection of the mfERG) latencies in the CH, R1 and R2. The differences in outer retinal areas (R3, R4) in the real smoking sessions and in all rings in the sham smoking sessions were not significant. Cigarette smoking may stimulate the central retinal areas in the acute phase. This effect may be related with the stimulant effect of nicotine on neurotransmission, deleterious effects on retinal and/or choroidal circulation, carbon monoxide toxicity and nicotine withdrawal.

Airway irritation and cough evoked by inhaled cigarette smoke: Role of neuronal nicotinic acetylcholine receptors

In a series of studies carried out in different experimental models, we investigated the type(s) of lung afferents and mechanism(s) underlying the cigarette smoke-induced airway irritation and cough. In healthy non-smokers, the intensity of airway irritation and cough evoked by cigarette smoke was markedly reduced after premedication with hexamethonium. A similar pattern of responses was also triggered by inhalation of nicotine aerosol. These studies in human subjects suggested nicotine as the primary causative agent in cigarette smoke that evokes airway irritation. Indeed, single-fiber recording experiments performed in anesthetized dogs showed that both C-fibers and rapidly adapting receptors in the lungs and airways were stimulated by inhalation of one puff of cigarette smoke, and the intensity of this stimulatory effect was related to the nicotine content in the cigarette and abolished by hexamethonium. To further study the direct effect of nicotine on these sensory nerves, we measured the change in intracellular calcium concentration ([Ca 2+] i) of pulmonary sensory neurons isolated from the nodose and jugular ganglia of adult rats. Our results showed that nicotine evoked an abrupt and transient increase in [Ca 2+] i in ∼34% of the 522 neurons tested, and 1,1-dimethyl-4-phenylpiperazinium, a selective agonist of the neuronal nicotinic acetylcholine receptors (NnAChRs), evoked a similar pattern of response as that of nicotine in these neurons. In conclusion, results of these studies show that nicotine exerts a direct stimulatory effect on vagal pulmonary sensory neurons. This stimulatory effect of nicotine is primarily responsible for the airway irritation and cough evoked by inhaled cigarette smoke, and is mediated through an activation of the NnAChRs.

Effects of drinking and smoking on endogenous levels of urinary γ-hydroxybutyric acid, a preliminary study

The aim of this study was to determine if the endogenous levels of γ-hydroxybutyric acid (GHB) in urine were affected by drinking and smoking. Urine samples were obtained from 20 healthy volunteers (15 males, 21–45 years; 5 females, 22–24 years). This population included four average drinkers (males), 4 average smokers (males), and 12 nonsmokers/nondrinkers (seven males and five females). Urinary levels of GHB were measured by gas chromatography. No gender differences were observed in the urinary levels of endogenous GHB. The urinary levels of GHB in males were 0.52±0.37 μg/ml in smokers, 0.28±0.21 μg/ml in nonsmokers/nondrinkers, and 0.23±0.04 μg/ml in drinkers. Urinary GHB levels were measured three times a day for 5 consecutive days in a male from each group. Large intra-individual differences were observed over the 5-day period in a smoker and a nonsmoker/nondrinker. No significant changes in daily endogenous GHB levels were observed in a drinker during the period. Our preliminary results suggest that stimulatory effects of nicotine on the central nervous system (CNS) may result in an increase in nocturnal formation of GHB and the depressive effects of ethanol on the CNS may not affect, even may inhibit, nocturnal production of GHB.

The κ-opioid receptor is involved in the stimulating effect of nicotine on adrenocortical activity but not in nicotine induced anxiety

The kappa (κ) opioid system appears to interact with nicotine in the modulation of locomotion and addiction related processes. In this study we have investigated the possible implication of the κ-opioid system in the effects of nicotine on anxiety and adrenocortical activity. In two different experiments, we analysed the possible interaction between nicotine (0.5 mg/kg i.p.) and either the κ-opioid receptor antagonist nor-binaltorphimine (5 mg/kg i.p.) or the κ-opioid receptor agonist U50,488H (1 mg/kg s.c.). Behavioural and endocrine experiments were performed in different groups of animals. Animals were exposed to the holeboard immediately followed by the plus-maze. Serum corticosterone levels were determined by radioimmunoassay. Nicotine induced an anxiogenic-like effect in the plus-maze and a significant decrease of holeboard activity. The anxiogenic-like effect in the plus-maze was not modified by any of the κ-opioid receptor ligands. Nicotine also induced a significant increase in the corticosterone levels, and the κ antagonist, which did not exert any effect per se, antagonised this effect. The κ-agonist U50,488H induced a significant increase in corticosterone concentration when administered alone. We provide the first evidence for the involvement of the κ-opioid receptor in the stimulatory effect of nicotine on adrenocortical activity.