Nicotine

Nicotinic acetylcholine receptors (nAChRs) mediate a variety of brain functions. Findings from postmortem studies and clinical investigations have implicated them in the pathophysiology and treatment of Alzheimer's and Parkinson's diseases and other CNS disorders (e.g. Tourette's syndrome, epilepsy, nicotine dependence). Therefore, it ultimately might be useful to image nAChRs noninvasively for diagnosis, for studies on how changes in nAChRs might contribute to cerebral disorders, for development of therapies targeted at nAChRs, and to monitor the effects of such treatments. To date, only (S)-(− )-nicotine, radiolabeled with 11 C, has been used for external imaging of nAChRs in human subjects. Since this radiotracer presents drawbacks, new ligands, with more favorable properties, have been synthesized and tested. Three general classes of compounds, namely, nicotine and its analogs, epibatidine and related compounds, and 3-pyridyl ether compounds, including A-85380, have been evaluated. Analogs of A-85380 appear to be the most promising candidates because of their low toxicity and high selectivity for the a4b2 subtype of nAChRs.

Molecular dynamics a b s t r a c t This study reports the comparative molecular modeling, docking and dynamic simulations of human a9a10 nicotinic acetylcholine receptors complexed with acetylcholine, nicotine and a-conotoxin RgIA, using as templates the crystal structures of Aplysia californica and Lymnaea stagnalis acetylcholine binding proteins. The molecular dynamics simulations showed that Arg112 in the complementary a10(À) subunit, is a determinant for recognition in the site that binds small ligands. However, Glu195 in the principal a9(+), and Asp114 in the complementary a10(À) subunit, might confer the potency and selectivity to a-conotoxin RgIA when interacting with Arg7 and Arg9 of this ligand.

Psychophysical methods were used to assess changes in the intensity of irritant sensations elicited by repeated application of capsaicin and nicotine delivered unilaterally to the tongue of human subjects. Whereas capsaicin (0.5 or 3 p.p.m.; repeated at 1 min intervals over 10 min) evoked progressively stronger ratings of irritation (sensitization), there was a significant decrement in irritation ratings (desensitization) to repeated application of nicotine (0.1%). A two-alternative forced-choice (2-AFC) procedure was additionally used to test for self-and cross-desensitization. After the subjects had received either repeated capsaicin or nicotine, a rest period ensued followed by the 2-AFC procedure. Either capsaicin or nicotine was delivered bilaterally to the tongue and subjects were asked to choose which side yielded a stronger sensation. Following capsaicin pretreatment, subjects reported that capsaicin evoked a stronger sensation on the previously untreated side (capsaicin self-desensitization). Similar self-desensitization was observed with nicotine. Furthermore, nicotine evoked a significantly weaker sensation on the side of the tongue pretreated with capsaicin (cross-desensitization). In contrast, capsaicin did not consistently evoke a weaker sensation on the nicotine-pretreated side, indicating an absence of cross-desensitization. These results are discussed in terms of physiological mechanisms that might underlie the contrasting sensory effects of nicotine versus capsaicin. Chem.

The extent and predictors of weight change were assessed among sustained nonsmoking special intervention participants in the Lung Health Study. The intervention included a 12-session group program and 2-mg nicotine gum. At 12 months, female sustained quitters (SQs; n = 248) ...

Perceptions of tobacco are a relatively unexplored issue in disadvantaged populations in India and France. The objectives of this study included the following: obtain qualitative information on representations of tobacco use and cessation within two vulnerable populations; identify cultural factors that influence tobacco use and cessation; and acquire information for the development of effective tobacco cessation strategies. A total of 21 focus groups were conducted in India and France. All study participants were disadvantaged adults 18 years old or older. Sixty women resided in South Delhi in India and 163 adults with disabilities resided in the south of France. They were all current tobacco users. Data were collected by focus group and analysed with thematic coding. In both samples, the most relevant reasons of tobacco use were daily life circumstances, which were also a major barrier to quitting. None of the participants reported that quitting difficulties could be due to depend...

In the isolated bronchial preparation of the guinea-pig, nicotine induced a contraction but not a relaxation. The contractile response of the bronchial preparation to nicotine was inhibited by hexamethonium and d-tubocurarine but not influenced by atropine and tetrodotoxin. In the isolated tracheal preparation of the guinea-pig where nicotine stimulated nicotinic receptor in nervous tissues, the contractile response to nicotine as considerably accelerated by the treatment of the guinea-pig with egg-albumin, while the contractile response of the bronchial preparation to nicotine was not influenced by the same treatment. These results suggest that a possible site of action of nicotine in the isolated bronchial preparation is not on the nervous cells but on the smooth muscle cells. However, we could not rule out a contribution by chemical mediators released by nicotine in the contractile mechanisms in the bronchial preparation.

Converging lines of evidence indicate the involvement of nicotinic acetylcholine receptors in depressive illness and antidepressant drug action. We investigated the effects of sub-chronic and chronic treatment with imipramine, nicotine and their combination on: (a) the ability of a dopamine-mimetic challenge to produce locomotor stimulation and (b) cortical density of h-adrenoceptors. One week of treatment with imipramine (10 mg/kg, twice daily) did not result in an altered response to the apomorphine (0.15 mg/kg) challenge, but after 2 weeks, the imipramine-treated rats demonstrated hyperactivity. Conversely, such increased locomotor response was observed in rats treated with nicotine (0.4 mg/kg, twice daily) for 1 but not for 2 weeks. Groups treated with nicotine + imipramine for 1 and 2 weeks demonstrated equally high hyperactivity in response to the apomorphine challenge. This effect was not different from the effects of 1-week treatment with nicotine or 2week treatment with imipramine. The density of h-adrenoceptors was equally decreased by 2 (but not 1) weeks of the treatment with imipramine, nicotine and their combination. The present behavioral and neurochemical data suggest the antidepressant-like effect of the chronic treatment with nicotine. It appears that the potentiation of the dopamine-mimetic-induced hyperactivity cannot be explained by hadrenoceptor down-regulation. D

Tobacco smoking has been correlated with a lower incidence of Alzheimer's disease (AD). This negative correlation has been attributed to nicotine's properties. However, the undesired side-effects of nicotine and the absence of clear evidence of positive effects of this drug on the cognitive abilities of AD patients have decreased the enthusiasm for its therapeutic use. In this review, we discuss evidence showing that cotinine, the main metabolite of nicotine, has many of the beneficial effects but none of the negative side-effects of its precursor. Cotinine has been shown to be neuroprotective, to improve memory in primates as well as to prevent memory loss, and to lower amyloid-beta (Aβ)) burden in AD mice. In AD, cotinine's positive effect on memory is associated with the inhibition of Aβ aggregation, the stimulation of pro-survival factors such as Akt, and the inhibition of pro-apoptotic factors such as glycogen synthase kinase 3 beta (GSK3β). Because stimulation of the α7 nicotinic acetylcholine receptors (α7nAChRs) positively modulates these factors and memory, the involvement of these receptors in cotinine's effects are discussed. Because of its beneficial effects on brain function, good safety profile, and nonaddictive properties, cotinine may represent a new therapeutic agent against AD.

Abstraet---Catecholamine secretion induced by various secretagogues in cultured bovine chromaffin cells has been correlated with Ca 2+ influx and intracellular Ca z+ concentrations. Nicotine and high K + caused prompt secretion of catecholamines from cells. Coincidently, both seeretagogues evoked 45[Ca2+] influx with a parallel increase in free intracellular Ca 2+ concentration, as determined by Quin 2 fluorescence. However, the rate of return of Ca 2+ level to baseline after nicotine stimulation was more rapid than after K + stimulation. In comparison, stimulation with veratridine produced a slow and prolonged Ca 2+ influx accompanied by lower levels of intracellular Ca 2+ than those observed after nicotine or K + stimulation. Yet, during 15 min of stimulation, veratridine induced a substantial catecholamine release, which was larger than that obtained after nicotine or K + stimulations. The Ca 2+ ionophore A23187 (1/~M) induced a pronounced increase in intracellular Ca 2+ levels, but did not evoke any significant catecholamine release. Finally, addition of the Ca 2 ÷ channel blocker verapamil following stimulation, at a time when intracellular Ca 2+ concentration was at its peak level, did not affect the rate of decline in intracellular free Ca 2+ concentration but promptly blocked Ca 2+ uptake and catecholamine secretion. These findings suggest that the rate of Ca 2+ influx, rather than the absolute level of intracellular Ca 2+ concentration, determines the rate and extent of catecholamine release.

We evaluated the eects of smoking on testicular function and fertilizing potential in rats. Twenty rats (group A) were exposed to the smoke of 20 cigarettes for 1 h per day. Ten rats (group B) were exposed to the smoke of 40 incense sticks for 1 h per day, and an additional 10 rats served as a control group (group C). After 10 weeks of daily exposure, serum levels of nicotine and cotinine were assessed, and a mating test was conducted. Five days later, serum concentrations of testosterone before and after human chorionic gonadotropin (hCG) stimulation, gonadotropins, and epididymal sperm content and motility were evaluated. In addition, in vitro fertilization was carried out. Nicotine and cotinine were detected in group A, but not in groups B and C. Basal serum testosterone and gonadotropin concentrations did not dier signi®cantly among the three groups, but the testosterone response to hCG stimulation was signi®cantly lower in group A than in groups B and C. Group A showed signi®cant reductions in epididymal sperm content and motility, and in fertility in vivo and in vitro. These ®ndings suggest that smoking leads to a secretory dysfunction of the Leydig cells, and also a de®ciency in sperm maturation and spermatogenesis. In addition, smoking has a detrimental eect on sperm fertilizing potentials in vivo and in vitro.

The ability of nicotine to decrease sensitivity to pain in humans has been a subject of dispute. Decreased sensitivity has been demonstrated in studies involving men, whereas the effect has been less obvious or absenl in studies involving predominantly, or entirely, women. To determine whether there are gender differences in nicotine's hypoalgcsic actions, ratings of electrocutaneous stimulation were obtained from 30 male and 44 female smokers and nonsmokers under placebo and nicotine conditions. Nicotine increased the pain threshold and tolerance ratings of men but had no effect on the pain ratings of women. Among men, there was no effect of smoking history, suggesting that the changes in pain perception reflect a direct pain-inhibitor)' effect of nicotine rather than a relief from acute nicotine withdrawal. Nicotine had no effect on mood or task ratings, indicating that the antinociceptive effects observed were not due to nicotine's putative mood effects.

In lampreys as in other vertebrates, brainstem centres play a key role in the initiation and control of locomotion. One such centre, the mesencephalic locomotor region (MLR), was identified physiologically at the mesopontine border. Descending inputs from the MLR are relayed by reticulospinal neurons in the pons and medulla, but the mechanisms by which this is carried out remain unknown. Because previous studies in higher vertebrates and lampreys described cholinergic cells within the MLR region, we investigated the putative role of cholinergic agonists in the MLR-controlled locomotion. The local application of either acetylcholine or nicotine exerted a direct dosedependent excitation on reticulospinal neurons as well as induced active or fictive locomotion. It also accelerated ongoing fictive locomotion. Choline acetyltransferase-immunoreactive cells were found in the region identified as the MLR of lampreys and nicotinic antagonists depressed, whereas physostigmine enhanced the compound EPSP evoked in reticulospinal neurons by electrical stimulation of this region. In addition, cholinergic inputs from the MLR to reticulospinal neurons were found to be monosynaptic. When the brainstem was perfused with D-tubocurarine, the induction of swimming by MLR stimulation was depressed, but not prevented, in a semi-intact preparation. Altogether, the results support the hypothesis that cholinergic inputs from the MLR to reticulospinal cells play a substantial role in the initiation and the control of locomotion.

The present study was conducted to determine if phenylpropanolamine (PPA) administered during the first week of nicotine termination could reduce or eliminate the body weight rebound which accompanies nicotine cessation. Sprague-Dawley rats were administered nicotine for 2 weeks after which they received either PPA or saline for 1 week. Control animals received saline during both drug periods. Body weight, food consumption, and water consumption were measured daily before drug, during nicotine and PPA administration, and for 14 days after PPA administration. In contrast to animals receiving saline upon termination of nicotine, animals receiving PPA did not gain weight at an accelerated rate. Termination of PPA did not result in a body weight rebound. To the extent that these results generalize to humans, they suggest that PPA could be used to reduce or eliminate postcessation weight gain in smokers who stop smoking.

Khat chewing/use, a green leaf with amphetamine-like effects is socially integrated in the Middle East and Africa. Khat chewing is often associated with tobacco smoking and occurs in closed places, such as a family home setting where the smoke-free laws cannot be implemented. Tobacco cigarette smoking among khat chewers is a significant concern, but there is also secondhand exposure to smoke at home or in places where khat users gather. Evidence suggests that e-cigarettes represent a significantly less harmful form of nicotine intake. Evaluating the effects of e-cigarettes among khat chewers could be important in understanding the impact of e-cigarettes as a harm reduction approach, with the potential to reduce the health risk associated with smoking.

N′-Nitrosonornicotine (NNN) is one of the most abundant strong carcinogens in unburned tobacco and cigarette smoke and is classified by the International Agency for Research on Cancer as carcinogenic to humans. Human exposure to NNN mainly occurs upon use of tobacco products. It is also possible that additional amounts of NNN are formed endogenously. The goal of this study was to evaluate the inhibitory effect of some antioxidants, including ascorbic acid and grape seed extract (GSE), on endogenous NNN formation in rats treated with nornicotine and sodium nitrite by gavage twice daily for 3 days. The study included four groups of rats: (1) negative control group A, to which no chemical was administered; (2) negative control group B, treated with nornicotine alone (2.5 µmol per gavage); (3) positive control group, to which both nornicotine (2.5 µmol per gavage) and sodium nitrite (7.5 µmol per gavage) were administered; and (4) rats treated with nornicotine (2.5 µmol per gavage), inhibitor (7.5 or 37.5 µmol per gavage), and sodium nitrite (7.5 µmol per gavage). The mean ((SD) total amount of NNN in the 3-day urine of rats treated with both nornicotine and sodium nitrite was 4.78 ( 2.88 nmol. The order of inhibition of endogenous NNN formation in rats at the molar ratio [nitrite]:[inhibitor] 1:5 was as follows: ascorbic acid (91%) > dihydroxyfumaric acid (86%) ≈ catechin (85%) > resveratrol (no inhibition). Treatment of rats with grape seed extract did not produce statistically significant inhibition of endogenous nornicotine nitrosation. This is the first study that demonstrates endogenous NNN formation in rats treated with nornicotine and sodium nitrite and effective inhibition of this process by ascorbic acid, dixydroxyfumaric acid, and catechin.

Rationale: To assess the success rate of smoking cessation with the ''minimal intervention strategy'' in general practice, and to determine the influence of spirometry on this success rate. Methods: Training in smoking cessation advice was given to 16 general practitioners (GPs). During 12 weeks, these GPs screened their practice population for smoking habits, the degree of dependence on nicotine, and the motivation to quit smoking. Patients willing to stop were randomised to a group that underwent a single office spirometry, or to a control group. The GPs were asked to support the attempts with the minimal intervention strategy. Success rates were compared after 6, 12 and 24 months. Results: On a population of 5590 patients, 1206 smokers were identified (22%). To the vulnerable group, identified following the Prochaska and Di Clemente scheme, the proposal was made to change smoking behaviour. Two hundred and twenty-one patients undertook an attempt of smoking cessation. Nicotine replacement therapy (NRT) or bupropion was prescribed in 51% of the attempts. Sixty-four sustained quitters were counted after 6 months (29%), 43 after 1 year (19%) and 33 after 2 years (15%). We found a small but statistically non-significant difference in success rate in favour of the group that underwent office spirometry. Conclusion: GPs can motivate almost 20% of their smoking population to quit smoking. The success rate with the minimal intervention strategy was 19% after 1 year and 15% after 2 years. We found no arguments in favour of confronting smokers with their lung function as a tool for enhancing smoking cessation.

An analytical procedure was developed and validated for the simultaneous identification and quantification of nicotine, cotinine, trans-3′-hydroxycotinine, and norcotinine in 0.5 mL of human oral fluid collected with the Quantisal™ oral fluid collection device. Solid phase extraction and liquid chromatography-tandem mass spectrometry with multiple reaction monitoring were utilized. Endogenous and exogenous interferences were extensively evaluated. Limits of quantification were empirically identified by decreasing analyte concentrations. Linearity was from 1 to 2,000 ng/mL for nicotine and norcotinine, 0.5 to 2,000 ng/mL for trans-3′hydroxycotinine, and 0.2 to 2,000 ng/mL for cotinine. Correlation coefficients for calibration curves were >0.99 and analytes quantified within ±13% of target at all calibrator concentrations. Suitable analytical recovery (>91%) was achieved with extraction efficiencies >56% and matrix effects <29%. This assay will be applied to the quantification of nicotine and metabolites in oral fluid in a clinical study determining the most appropriate nicotine biomarker concentrations differentiating active, passive, and environmental nicotine exposure.

To explore why some African-American smokers choose not to use nicotine replacement therapy (NRT) when attempting smoking cessation. Semistructured audiotaped qualitative telephone interviews. Thirty-three participants who were enrolled in a five-week cessation program were offered free NRT. Participants were asked to share their experiences and perceptions about trying to quit smoking. Data related to NRT perceptions were analyzed using an interpretive approach. Participant comments suggested two issues that may help explain why some African-American smokers do not use NRT when attempting cessation. First, many participants expressed concerns about the nicotine dose in NRT and worried that using it would increase nicotine dependence. Second, there was considerable discussion about NRT&#39;s ambiguous status as a &quot;drug&quot; (along with sometimes-unrealistic expectations for its efficacy independent of human effort) and concern about lack of control over drug delivery and absor...

This multicenter, randomized, open-label clinical trial was conducted to determine whether the combined use of nicotine patch therapy and a nicotine nasal spray would improve smoking abstinence rates compared to either treatment alone, without behavioral counseling. Data were collected at 15 regional cancer control oncology centers within the North Central Cancer Treatment Group. Of the 1384 smokers randomized to the study, 20% were abstinent from smoking at 6 weeks and 8% were abstinent at 6 months. At 6 weeks, the 7-day point prevalence smoking abstinence rate for the patch alone (21.1%) was superior to the spray (13.6%) but was significantly lower than the rate for combination therapy (27.1%). At 6 months, the 7-day point prevalence abstinence rates were not significantly different among the three groups. Combination nicotine nasal spray and nicotine patches were delivered safely in a nonspecialized outpatient clinical setting and enhanced short-term smoking abstinence rates, but these rates were not sustained at 6 months.

To determine which glutamate receptor (GluR) subtypes are responsible for glutamate-induced excitotoxicity in cultured adult pig retinal ganglion cells (RGCs) and to characterize the neuroprotective effect of acetylcholine (ACh) on pig RGCs. METHODS. Adult pig RGCs were isolated from other retinal tissue by a modified panning technique using Thy 1.1 antibody. Isolated RGCs were cultured in control media and media containing: glutamate, NMDA, or KA; glutamate and CNQX, MK-801, or AP-7; ACh, nicotine or muscarine; ACh and ␣-bungarotoxin (Bgt) or methyllycaconitine (MLA); and glutamate and choline or glutamate, choline, and MLA. To determine cell viability, cells were loaded with calcein and counted. RESULTS. Ninety-eight percent of isolated cells were immunolabeled with Thy 1.1 antibody. Chronic exposure to 500 M glutamate decreased the number of surviving large and small RGCs, compared to control conditions. This glutamate-induced excitotoxicity was mediated through both NMDA and non-NMDA GluRs. In neuroprotective studies, ACh, nicotine, and choline significantly reduced glutamate-induced excitotoxicity in adult pig RGCs through ␣-Bgt-sensitive nicotinic ACh receptors (nAChRs). DISCUSSION. This was the first report of a modified panning technique to isolate adult pig RGCs. Cell viability was relatively high using this method, and both large and small RGCs grew extensive neurites in culture. The finding that both NMDA and non-NMDA GluRs were involved in glutamate-induced excitotoxicity suggests that isolated pig RGCs provide a good model for glaucoma. In addition, activation of AChRs may be useful in protecting RGC from excitotoxic insults occurring in neurodegenerative diseases such as glaucoma. (Invest Ophthalmol Vis Sci. 2004;45:1531-1543

Stimulation of nicotinic acetylcholine receptors (nAChR) excites peripheral sensory nerve fibres, but also exert antinociceptive effects. The differences in these nAChR-mediated effects could be related to the expression of different nAChR subtypes located on nociceptive neurons. In the present study, we focused on the recently described a10-nAChR subunit, and on a4 and a7 subunits, which are the most abundant subunits in the central nervous system. In nociceptive neurons from thoracic and lumbar dorsal root ganglia (DRG), nAChR subunits were found at transcriptional (RT-PCR), translational (immunohistochemistry) and functional levels. Cultured DRG neurons express mRNA for the subunits a2-7 and a10. The a-subunit proteins 4, 7 and 10 were colocalised in virtually all nociceptive neurons that were identified by immunoreactivity for the vanilloid receptor TRPV-1. These findings were corroborated by current recordings and calcium measurements, which revealed excitatory inward currents and calcium responses in capsaicin sensitive neurons.

The principal sites for biological action of tobacco products are thought to be the nicotinic acetylcholine receptors (nAChR). Nicotinic receptor subunit genes, therefore, represent an important gene family for study in nicotine addiction. They are localized in both brain and in the periphery. In brain these receptors appear to function as modulators of synaptic transmission; the function of peripheral receptors is not known. Nicotinic receptor levels in human brain are regulated by smoking in a dose-dependent manner. In peripheral blood, nicotinic receptors are present on both lymphocytes and polymorphonuclear cells (PMN). We have compared [ 3 H]nicotine binding in PMN isolated from smokers and non-smokers. [ 3 H]nicotine binding was increased in smokers and was correlated, as in brain, with tobacco use. Expression of both mRNA and protein in lymphocytes and PMN, for a subset of nicotinic receptor subunits, suggests that these cell types contain both α4β2 and α3β4 receptors.

The effect of an indole-alkaloid mitragynine isolated from the Thai medicinal herb kratom (Mitragyna speciosa) on neurogenic contraction of smooth muscle was studied in guinea-pig vas deferens. Mitragynine inhibited the contraction of the vas deferens produced by electrical transmural stimulation. On the other hand, mitragynine failed to affect the responses to norepinephrine and ATP. Mitragynine did not reduce KCl-induced contraction in the presence of tetrodotoxin, prazosin and a,h-methylene ATP. Mitragynine inhibited nicotine-or tyramine-induced contraction. By using the patch-clamp technique, mitragynine was found to block T-and L-type Ca 2+ channel currents in N1E-115 neuroblastoma cells. In the Ca 2+ measurement by a fluorescent dye method, mitragynine reduced KCl-induced Ca 2+ influx in neuroblastoma cells. The present results suggest that mitragynine inhibits the vas deferens contraction elicited by nerve stimulation, probably through its blockade of neuronal Ca 2+ channels. D

The present methodology was developed to simultaneously assess chronic exposure to PAHs and to tobacco from the analysis of one hair specimen per examined individual. The method is a two step extraction of twelve mono-hydroxy-PAHs and of nicotine, and their separate analysis by optimized methods using gas chromatography-negative chemical ionization-mass spectrometry. After method validation and assessment of the hair decontamination procedure, 105 hair specimens from smokers and nonsmokers were analyzed. All the hair samples tested positive for nicotine. Median concentration was 10.7 ng/mg for smokers and 0.5 ng/mg for non-smokers. 70% of the samples tested positive for OH-PAHs. The most common one was 2-naphthol (61%) and its concentration was significantly higher in smokers than in non-smokers (median: 111 vs 70 pmol/g, p = 0.006). 2-OH-benzo(c)phenanthrene and 6-OH-chrysene were only detected once in a non-smoker's hair. The concentration of the sum of all PAHmetabolites ranged from 24 to 67190 pmol/g (median: 118 pmol/g). Only six samples tested positive for more than two different metabolites. The simultaneous detection of nicotine and OH-PAHs in hair is possible and provides reliable results. This represents a useful tool for the accurate biomonitoring of chronic exposure to PAH and correct identification of the sources of exposure.

Recent advances in studies of nicotinic agents in humans have begun to more carefully define cognitive operations that can be influenced by nicotinic stimulation and/or blockade. Careful separation of the cognitive domains affected by nicotinic stimulation has identified attentional performance as the most likely candidate to be positively influenced by nicotinic receptor activation. Studies of the effects of nicotinic systems and/or nicotinic receptor stimulation in pathological disease states such as Alzheimer's disease, Parkinson's disease, attention deficit/ hyperactivity disorder and schizophrenia show the potential for therapeutic utility of nicotinic drugs. In contrast to studies in pathological states, studies of nicotine in normal-non-smokers tend to show deleterious effects. This contradiction can be resolved by consideration of cognitive and biological baseline dependency differences between study populations in terms of the relationship of optimal cognitive performance to nicotinic receptor activity. Although normal individuals are unlikely to show cognitive benefits after nicotinic stimulation except under extreme task conditions, individuals with a variety of disease states can benefit from nicotinic drugs. Attentional function/ dysfunction may serve as an endophenotypic therapeutic target for nicotinic drug development.

The effect of an indole-alkaloid mitragynine isolated from the Thai medicinal herb kratom (Mitragyna speciosa) on neurogenic contraction of smooth muscle was studied in guinea-pig vas deferens. Mitragynine inhibited the contraction of the vas deferens produced by electrical transmural stimulation. On the other hand, mitragynine failed to affect the responses to norepinephrine and ATP. Mitragynine did not reduce KCl-induced contraction in the presence of tetrodotoxin, prazosin and a,h-methylene ATP. Mitragynine inhibited nicotine-or tyramine-induced contraction. By using the patch-clamp technique, mitragynine was found to block T-and L-type Ca 2+ channel currents in N1E-115 neuroblastoma cells. In the Ca 2+ measurement by a fluorescent dye method, mitragynine reduced KCl-induced Ca 2+ influx in neuroblastoma cells. The present results suggest that mitragynine inhibits the vas deferens contraction elicited by nerve stimulation, probably through its blockade of neuronal Ca 2+ channels. D

Parkinson's disease (PD) affects one in every 100 persons above the age of 65 years, making it the second most common neurodegenerative disease after Alzheimer's disease. PD is a disease of the central nervous system that leads to severe difficulties with body motions. The currently available therapies aim to improve the functional capacity of the patient for as long as possible; however they do not modify the progression of the neurodegenerative process. The need for newer and more effective agents is consequently receiving a great deal of attention and consequently being subjected to extensive research. This review concisely compiles the limitations of currently available therapies and the most recent research regarding neuroprotective agents, antioxidants, stem cell research, vaccines and various surgical techniques available and being developed for the management of PD.

Numerous studies have indicated a correlation between ethanol intake and cigarette smoking in heavy drinkers. We have studied the underlying pharmacological basis of this relationship using cultured rat cortical neurons. These neurons express nicotinic receptors having characteristics similar to those described for the a482 subunit combination. In the presence of a-bungarotoxin both acetylcholine (ACh) and nicotine evoked currents with respective E C , values of 4.3 and 3.4 pM. The maximal nicotine-activated response, however, was only 56% that of the maximal ACh current. It was previously shown that 10 to 100 mM of ethanol potentiated ACh-mediated currents in these neurons. We demonstrate that 100 mM ethanol similarly potentiates currents evoked by 300 nM (40%) and 1 pM nicotine (61 Oh). This suggests that an ethanol-induced potentiation of nicotinic currents may enhance the acute positive reinforcement associated with nicotine and could increase tobacco use during heavy ethanol intake. However, further experimentation indicated that the continuous perfusion of 30, 100, or 300 nM nicotine desensitizes ACh-evoked currents by 38, 54, and 62%, respectively, with little direct receptor-channel activation. The residual ACh currents of nicotine-desensitized receptor channels were potentiated by 100 mM ethanol to nearly the extent as were the undesensitized control responses. We propose that the opposing effect of ethanol on nicotine-induced desensitization could also explain the increased tobacco use observed with excessive drinking. Thus, ethanol has a dual effect regarding nicotine. It enhances acute nicotine-mediated receptor activation, although opposing the net effect of nicotineinduced receptor channel desensitization.

Rationale: A great deal of research supports the role of nicotine in cigarette addiction. However, the effectiveness of nicotine replacement therapy (NRT) as a smoking cessation treatment has fallen short of initial hopes. A key reason may be that NRT does not address nonnicotine components of smoking reinforcement. These include constituents that provide reinforcing sensory stimulation, components that minimize excessive irritation from inhaled nicotine and other pharmacologically active compounds in cigarette smoke. Objective: Studies using various paradigms to dissociate nicotine from other components of smoking are summarized. Results: Nonnicotine components provide many rewarding effects, often surpassing the direct effects of nicotine. Substitutes for the sensory effects of smoking may be effective in relieving craving for cigarettes and in facilitating smoking cessation. Moreover, techniques for devaluing smoking-related cues may decrease craving and enhance subsequent abstinence. Promising approaches for devaluing smoke cues include extinction-based treatments employing denicotinized cigarettes and the use of nicotinic agonist and/or antagonist treatment during the weeks leading up to a quit attempt. Recent studies suggest that incorporating these approaches into a treatment program may significantly increase smoking abstinence rates. Preliminary findings also suggest that replacement of the effects of monoamine oxidase inhibitors contained in cigarette smoke may enhance quit rates. Conclusions: While current NRT methods have been the mainstay of smoking cessation treatment and will likely continue to serve a useful role, the next stage of progress will likely entail the development of tools designed with recognition of the importance of nonnicotine components of cigarette smoking.

Individuals are different 'chronotypes' with early 'larks' and late 'owls' forming the limits of a normal distribution in the population. We recently described that late chronotypes who suffer from a conflict between internal and external time ('social jetlag') suffer from more mental distress and are more likely to smoke than early chronotypes (Wittmann, Dinich, Merrow, and Roenneberg, 2006. Social jetlag: mis-alignment of biological and social time. Chronobiology International, 23:497-509.). We performed a detailed analysis of the same database collected in 2002 comprising 134 daily smokers and 366 nonsmokers, scrutinizing the relationships between chronotype, smoking, and alcohol consumption as well as psychological well-being using a multiple mediation analysis. On average, smokers tend to be later chronotypes, report more sleep-associated psychosomatic symptoms, are more depressed, less balanced, and less vigilant. The mediation analysis suggests that only those late chronotypes who smoke and those who drink more suffer from increased psychological distress. We suggest that 'chronotype' is introduced as an additional factor in substance use, that is, when considering motives for smoking and drinking.

Rationale Nicotine has been shown in a variety of studies in humans and experimental animals to improve cognitive function. Nicotinic treatments are being developed as therapeutic treatments for cognitive dysfunction. Objectives Critical for the development of nicotinic therapeutics is an understanding of the neurobehavioral bases for nicotinic involvement in cognitive function. Methods Specific and diverse cognitive functions affected by nicotinic treatments are reviewed, including attention, learning, and memory. The neural substrates for these behavioral actions involve the identification of the critical pharmacologic receptor targets, in particular brain locations, and how those incipient targets integrate with broader neural systems involved with cognitive function. Results Nicotine and nicotinic agonists can improve working memory function, learning, and attention. Both α4β2 and α7 nicotinic receptors appear to be critical for memory function. The hippocampus and the amygdala in particular have been found to be important for memory, with decreased nicotinic activity in these areas impairing memory. Nicotine and nicotinic analogs have shown promise for inducing cognitive improvement. Positive therapeutic effects have been seen in initial studies with a variety of cognitive dysfunctions, including Alzheimer's disease, age-associated memory impairment, schizophrenia, and attention deficit hyperactivity disorder. Conclusions Discovery of the behavioral, pharmacological, and anatomic specificity of nicotinic effects on learning, memory, and attention not only aids the understanding of nicotinic involvement in the basis of cognitive function, but also helps in the development of novel nicotinic treatments for cognitive dysfunction. Nicotinic treatments directed at specific receptor subtypes and nicotinic cotreatments with drugs affecting interacting transmitter systems may provide cognitive benefits most relevant to different syndromes of cognitive impairment such as Alzheimer's disease, schizophrenia, and attention deficit hyperactivity disorder. Further research is necessary in order to determine the efficacy and safety of nicotinic treatments of these cognitive disorders.

fully honest, I enjoy one or two Havana cigars per year). Ecigarettes comprise a number of devices, which typically use a battery to heat a cartridge with a nicotin-containing solution ("e-liquid" or "e-juice"), which is thus vaporized for inhalation. The first-generation devices are disposable or rechargeable. The second-generation e-cigarettes contain tank systems with larger batteries for prolonged use. Finally, the third-generation consists of large-capacity batteries and integrated circuits, allowing users to control the amount of nicotine per puff. Thus, the newer generation tools alleviate the concern about billions of small batteries ending in our trash somewhat. E-cigarettes are taking over the market with an astonishing pace. They started only about ten years ago as a spin-off from advances in battery technology from mobile phones, which can now provide sufficient power to vaporize an adequate flow of liquid and sufficient battery life to make devices practical 2. In

The health consequences of tobacco smoking disproportionately affect African Americans, but research on whether efficacious interventions can be generalized to this population is limited. This study examined the efficacy of group-based cognitive-behavioral therapy (CBT) for smoking cessation among African Americans. Method: Participants (N ϭ 154; 65% female, M ϭ 44 years old, mean cigarettes/ day ϭ 13) were randomly assigned to either (a) group CBT or (b) group general health education (GHE). Participants in both conditions received 6 sessions of counseling and 8 weeks of transdermal nicotine patches. The primary outcome variable was 7-day point prevalence abstinence (ppa), assessed at the end of counseling (2 weeks) and at 3-and 6-month follow-ups. Secondary outcomes included 24-hr ppa and 28-day continuous abstinence (assessed at 3 and 6 months). Results: Intent-to-treat analyses demonstrated the hypothesized effects, such that 7-day ppa was significantly greater in the CBT than the GHE condition at the end of counseling (51% vs. 27%), at 3 months (34% vs. 20%), and at 6 months (31% vs. 14%). Results of a generalized linear mixed model demonstrated a significant effect of CBT versus GHE on 7-day ppa (odds ratio ϭ 2.57, 95% CI [1.40, 4.71] and also an effect of time ( p Ͻ .002). The Condition ϫ Time interaction was not significant. Similar patterns of results emerged for 24-hour ppa and 28-day continuous abstinence. Results from per protocol analyses (i.e., participants who completed all aspects of the study) corroborate the intent-to-treat findings. Conclusions: These results demonstrate that intensive, group CBT smoking cessation interventions are efficacious among African American smokers.

Ulcerative colitis (UC), a subcategory of inflammatory bowel disease, afflicts 1-2 million people in the United States, and many more worldwide. Although the exact cause of ulcerative colitis remains undetermined, the condition appears to be related to a combination of genetic and environmental factors. While conventional treatments can be effective in maintaining remission and decreasing the length of active disease periods, the treatments are not without side effects, and a significant number of people suffering from UC fail to respond to even the strongest drugs. This article reviews potential unconventional treatments - transdermal nicotine, heparin, melatonin, DHEA, probiotics, fiber, dietary changes, botanicals, essential fatty acids, and other nutrients - that may be considered in conjunction with conventional approaches or as part of a comprehensive alternative treatment protocol. In addition this review addresses risk factors, pathogenesis, nutrient deficiencies, convention...

Despite the wide-ranging and authoritative 1988 review by the US Surgeon General, views questioning the addictiveness of nicotine contine to be expressed in some quarters. This lack of complete consensus is not unexpected, since no universally agreed scientific definition of addiction exists. In this paper we briefly consider a number of lines of evidence from both the human and animal literature bearing on the addictiveness of nicotine. Patterns of use by smokers and the remarkable intractability of the smoking habit point to compulsive use as the norm. Studies in both animal and human subjects have shown that nicotine can function as reinforcer, albeit under a more limited range of conditions than with some other drugs of abuse. In drug discrimination paradigms there is some cross-generalisation between nicotine on the one hand, and amphetamine and cocaine on the other. A welldefined nicotine withdrawal syndrome has been delineated which is alleviated by nicotine replacement. Nicotine replacement also enhances outcomes in smoking cessation, roughly doubling success rates. In total, the evidence clearly identifies nicotine as a powerful drug of addiction, comparable to heroin, cocaine and alcohol.