Efficacy Of Nicotine Research Articles

Functional Impact of 14 Single Nucleotide Polymorphisms Causing Missense Mutations of Human α7 Nicotinic Receptor.

The α7nicotinic receptor (nAChR) is a major subtype of the nAChRs in the central nervous system, and the receptor plays an important role in brain function. In the dbSNP database, there are 55 single nucleotide polymorphisms (SNPs) that cause missense mutations of the human α7nAChR in the coding region. In this study, we tested the impact of 14 SNPs that cause missense mutations in the agonist binding site or the coupling region between binding site and channel gate on the receptor function. The wild type or mutant receptors were expressed or co-expressed in Xenopus oocytes, and the agonist-induced currents were tested using two-electrode voltage clamp. Our results demonstrated that 6 mutants were nonfunctional, 4 mutants had reduced current expression, and 1 mutants altered ACh and nicotine efficacy in the opposite direction, and one additional mutant had slightly reduced agonist sensitivity. Interestingly, the function of most of these nonfunctional mutants could be rescued by α7nAChR positive allosteric modulator PNU-120596 and agonist-PAM 4BP-TQS. Finally, when coexpressed with the wild type, the nonfunctional mutants could also influence the receptor function. These changes of the receptor properties by the mutations could potentially have an impact on the physiological function of the α7nAChR-mediated cholinergic synaptic transmission and anti-inflammatory effects in the human SNP carriers. Rescuing the nonfunctional mutants could provide a novel way to treat the related disorders.

E-cigarettes and smoking cessation: evidence from a systematic review and meta-analysis.

BackgroundE-cigarettes are currently being debated regarding their possible role in smoking cessation and as they are becoming increasingly popular, the research to date requires investigation.ObjectivesTo investigate whether the use of e-cigarettes is associated with smoking cessation or reduction, and whether there is any difference in efficacy of e-cigarettes with and without nicotine on smoking cessation.Data SourcesA systematic review of articles with no limit on publication date was conducted by searching PubMed, Web of Knowledge and Scopus databases.MethodsPublished studies, those reported smoking abstinence or reduction in cigarette consumption after the use of e-cigarettes, were included. Studies were systematically reviewed, and meta-analyses were conducted using Mantel-Haenszel fixed-effect and random-effects models. Degree of heterogeneity among studies and quality of the selected studies were evaluated.ResultsSix studies were included involving 7,551 participants. Meta-analyses included 1,242 participants who had complete data on smoking cessation. Nicotine filled e-cigarettes were more effective for cessation than those without nicotine (pooled Risk Ratio 2.29, 95%CI 1.05-4.97). Amongst 1,242 smokers, 224 (18%) reported smoking cessation after using nicotine-enriched e-cigarettes for a minimum period of six months. Use of such e-cigarettes was positively associated with smoking cessation with a pooled Effect Size of 0.20 (95%CI 0.11-0.28). Use of e-cigarettes was also associated with a reduction in the number of cigarettes used.LimitationsIncluded studies were heterogeneous, due to different study designs and gender variation. Whilst we were able to comment on the efficacy of nicotine vs. non-nicotine e-cigarettes for smoking cessation, we were unable to comment on the efficacy of e-cigarettes vs. other interventions for cessation, given the lack of comparator groups in the studies included in this meta-analysis.ConclusionsUse of e-cigarettes is associated with smoking cessation and reduction. More randomised controlled trials are needed to assess effectiveness against other cessation methods.

SY22-5 * NICOTINE AND COGNITION IN SCHIZOPHRENIA

Nicotine binds to presynaptic nicotinic acetylcholine receptors (nAChRs) in the brain and facilitates the release of acetylcholine, dopamine, serotonin, glutamate and other neurotransmitters known to be involved in cognitive processes. Nicotine systems in the brain play an important role in the neural basis of memory and attention. Smoking is highly prevalent in schizophrenia, and there is evidence for beneficial effects on neurocognition. Nicotine exposure to non-smoking schizophrenia patients and nicotine application after abstinence to smoking schizophrenia improved attention deficits. The study analyzing the interactional effects of diagnosis of schizophrenia and smoking history suggested a positive effect of smoking history on divided attention in schizophrenia patients. Clinical studies using transdermal nicotine patches have demonstrated the efficacy of nicotine in improving cognitive performance, particularly sustained attention in nonsmokers with schizophrenia. Mecamylamine, a nAChR antagonist, worsened performance of attention compared to varenicline, a nAChR partial agonist, in schizophrenia. There was a treatment by diagnosis interaction, such that mecamylamine worsened performance of sustained attention compared to placebo and varenicline in schizophrenia patients, effects not observed in controls. These findings support a role for nAChRs in attention and suggest that those with schizophrenia may be particularly sensitive to nAChR blockade.

Menthol Suppresses Nicotinic Acetylcholine Receptor Functioning in Sensory Neurons via Allosteric Modulation

In this study, we have investigated how the function of native and recombinant nicotinic acetylcholine receptors (nAChRs) is modulated by the monoterpenoid alcohol from peppermint (−) menthol. In trigeminal neurons (TG), we found that nicotine (75 μM)-activated whole-cell currents through nAChRs were reversibly reduced by menthol in a concentration-dependent manner with an IC50 of 111 μM. To analyze the mechanism underlying menthol's action in more detail, we used single channel and whole-cell recordings from recombinant human α4β2 nAChR expressed in HEK tsA201 cells. Here, we found a shortening of channel open time and a prolongation of channel closed time, and an increase in single channel amplitude leading in summary to a reduction in single channel current. Furthermore, menthol did not affect nicotine's EC50 value for currents through recombinant human α4β2 nAChRs but caused a significant reduction in nicotine's efficacy. Taken together, these findings indicate that menthol is a negative allosteric modulator of nAChRs.

Efficacy of a Nicotine (4 mg)-Containing Lozenge on the Cognitive Impairment of Nicotine Withdrawal

Controversy exists over the effect of tobacco deprivation in nicotine-dependent individuals and the efficacy of nicotine in reversing performance decrements. This study's aim was to assess the efficacy of nicotine (4-mg lozenge) versus placebo on aspects of cognitive and psychomotor performance, mood, and withdrawal symptoms in male and female established smokers. Male and female smokers (N = 22; mean age, 28.8 years), with a smoking history of more than 1 year and time to first cigarette of less than 30 minutes upon waking, were enrolled. Baseline measures were obtained at 17 hours of abstinence. At 18-hour abstinence, nicotine or placebo was administered every 2 hours over an 8-hour period. Cognitive and psychomotor performance measurements were taken 30 minutes after dose. Cognitive test battery included Rapid Visual Information Processing, Continuous Tracking Task, Critical Flicker Fusion, Choice Reaction Time, Stroop Test, and Sternberg's Short-term Memory Scanning Task. Withdrawal (Modified Minnesota Withdrawal Scale) and mood (Positive and Negative Affect Schedule) were also assessed. A mixed-models analysis of covariance was performed. Compared with placebo nicotine (4 mg) significantly improved vigilance, divided attention, executive functioning, working memory, and sensorimotor performance in abstinent volunteers (P < or = 0.05). Withdrawal symptoms including craving, difficulty concentrating, irritability, and restlessness were also attenuated, and affective state was improved after nicotine 4 mg administration. Compared with placebo, nicotine (4 mg) improved measures of vigilance, memory, and attention; improved mood; and reduced withdrawal symptoms. These findings suggest that repeated nicotine replacement therapy over a period of 8 hours can improve cognitive deficits associated with nicotine withdrawal.

Treatment of classic Kaposi sarcoma with a nicotine dermal patch: a phase II clinical trial

Kaposi sarcoma (KS), a malignancy of dermal endothelial cells that is caused by human herpesvirus 8 (HHV8) infection, is sensitive to perturbations of immunity. Nicotine might be effective against KS because of its immunologic and vascular effects and because smoking is associated with a low risk of KS. We conducted a masked, randomized phase 2 clinical trial of transdermal nicotine and placebo patches to assess the safety and efficacy of nicotine against classic KS (cKS). Three cKS lesions, predominantly nodules, in each of 24 non-smoking patients were randomly assigned to 15 weeks continuous treatment with nicotine patch (escalated to 7 mg), identical masked placebo patch or no patch. Changes in lesion area and elevation from baseline through six follow-up visits, by direct measurement and by two independent readers using digital photographs of the lesions, were compared using non-parametric and regression methods. Changes in longitudinal levels of HHV8 antibodies and DNA in blood cells were similarly assessed. There were no systemic or serious adverse events, and compliance was good. One patient resumed smoking and discontinued patches, and two patients withdrew at week 12 for unrelated indications. Six (29%) of the remaining 21 suspended use of patches to relieve local skin irritation; four of these six completed the trial at reduced dose. Treatment assignment was not associated with significant or consistent changes in cKS lesion area or elevation, HHV8 viral load or antibodies. Transdermal nicotine and placebo patches caused no serious toxicities but had no demonstrable effect on nodular cKS lesions or HHV8 levels.

Development of an anti-cotinine vaccine to potentiate nicotine-based smoking cessation strategies

Nicotine replacement therapies (NRT) have limited success in smoking cessation. The efficacy of nicotine may be compromised by its main metabolite, cotinine. An anti-cotinine vaccine to remove this antagonism could enhance the efficacy of NRT. We show that cotinine is a weak nicotinic agonist and decreases responses to nicotine, consistent with antagonism through receptor desensitisation. trans-4-Thiol cotinine was coupled to tetanus toxoid, and rats immunised repeatedly. Vaccination raised antibodies specific for cotinine that do not recognise other metabolites or nicotine. Increased serum cotinine concentrations following nicotine administration indicate sequestration of cotinine by antibodies, encouraging further evaluation of this vaccine in behavioural models of nicotine addiction and relapse.

Developmental regulation of nicotinic acetylcholine receptors within midbrain dopamine neurons

We have combined anatomical and functional methodologies to provide a comprehensive analysis of the properties of nicotinic acetylcholine receptors (nAChRs) on developing dopamine (DA) neurons of Sprague–Dawley rats. Double-labeling in situ hybridization was used to examine the expression of nAChR subunit mRNAs within developing midbrain DA neurons. As brain maturation progressed there was a change in the pattern of subunit mRNA expression within DA neurons, such that α3 and α4 subunits declined and α6 mRNA increased. Although there were strong similarities in subunit mRNA expression in substantia nigra (SNc) and ventral tegmental area (VTA), there was higher expression of α4 mRNA in SNc than VTA at gestational day (G) 15, and of α5, α6 and β3 mRNAs during postnatal development. Using a superfusion neurotransmitter release paradigm to functionally characterize nicotine-stimulated release of [ 3H]DA from striatal slices, the properties of the nAChRs on DA terminals were also found to change with age. Functional nAChRs were detected on striatal terminals at G18. There was a decrease in maximal release in the first postnatal week, followed by an increase in nicotine efficacy and potency during the second and third postnatal weeks. In the transition from adolescence (postnatal days (P) 30 and 40) to adulthood, there was a complex pattern of functional maturation of nAChRs in ventral, but not dorsal, striatum. In males, but not females, there were significant changes in both nicotine potency and efficacy during this developmental period. These findings suggest that nAChRs may play critical functional roles throughout DA neuronal maturation.

Exploitation of the nicotinic anti-inflammatory pathway for the treatment of epithelial inflammatory diseases

Discoveries in the first few years of the 21st century have led to an understanding of important interactions between the nervous system and the inflammatory response at the molecular level, most notably the acetylcholine (ACh)-triggered, alpha7-nicotinic acetylcholine receptor (alpha7nAChR)-dependent nicotinic anti-inflammatory pathway. Studies using the alpha7nAChR agonist, nicotine, for the treatment of mucosal inflammation have been undertaken but the efficacy of nicotine as a treatment for inflammatory bowel diseases remains debatable. Further understanding of the nicotinic anti-inflammatory pathway and other endogenous anti-inflammatory mechanisms is required in order to develop refined and specific therapeutic strategies for the treatment of a number of inflammatory diseases and conditions, including periodontitis, psoriasis, sarcoidosis, and ulcerative colitis.

Halogenated cytisine derivatives as agonists at human neuronal nicotinic acetylcholine receptor subtypes

Cytisine (cy) is a potent and competitive partial agonist at α4 subunit-containing nicotinic acetylcholine (nACh) receptors while at homomeric α7-nACh receptors it behaves as a full agonist with a relatively lower potency. In the present study, we assessed the effects of bromination or iodination of the pyridone ring of cy and N-methylcytisine ( N-Me-cy) on the effects of these compounds on recombinant human (h) α7, hα4β2 and hα4β4 nACh receptors expressed in clonal cell lines and Xenopus oocytes. Halogenation at C(3) of cy or N-Me-cy usually brings about a marked increase in both affinity and efficacy at hα7, hα4β2 and hα4β4 nACh, the extent of which depends on whether the halogen is bromine or iodine, and upon receptor subtype. The effects of halogenation at C(5) are strongly influenced by the specific halogen substituent so that bromination causes a decrease in both affinity and efficacy while iodination decreases affinity but its effects on efficacy range from a decrease (hα7, hα4β4 nACh receptors) to a marked increase (hα4β2 nACh receptors). Based on these findings, which differ from those showing that neither the affinity nor efficacy of nicotine, 3-(2-azetidinylmethoxy)-pyridine or epibatidine are greatly affected by halogenation, dehalogenation or halogen exchange at equivalent positions, we suggest that cy, N-Me-cy and their halo-isosteres bind to neuronal nACh receptors in a different orientation allowing the halogen atom to interact with a hydrophobic halogen-accepting region within the predominantly hydrophobic agonist-binding pocket of the receptors.

Efficacy of nicotine in refractory distal colitis

Efficacy of nicotine in refractory distal colitis

Endogenous opioids and smoking: a review of progress and problems.

The present report examines efforts to elucidate the role of opioid mechanisms in the reinforcement of smoking. A number of approaches have been used to evaluate nicotine-opioid interactions. Opiate agonists such as heroin or methadone have been found to increase cigarette smoking reliably in humans, and morphine has been shown to increase the potency and efficacy of nicotine in rats. There is also an extensive literature documenting the nicotine-stimulated release of endogenous opioids in various brain regions involved in the mediation of opiate reinforcement. Blockade studies using opioid antagonists have not been as conclusive. Although animal models have demonstrated commonalities between nicotine withdrawal and the opiate abstinence syndrome, including reversibility by morphine, and although the impact of nicotine on certain response systems such as respiratory reflexes has clearly been shown to involve opioid mediation, attempts to demonstrate opioid modulation for the key indicators of smoking reinforcement--cigarette consumption and nicotine self-administration--have been fraught with difficulty. Resolution of the apparent contradictions will require taking into account: (a) the biphasic properties of nicotine-opioid effects at higher doses and anti-opioid effects at lower doses; (b) the contributions of the opioid receptor populations--mu, kappa, sigma--stimulated at various dose levels; (c) the possibility that endogenous-opioid activity is entrained primarily during the acquisition or re-acquisition of nicotine self-administration; (d) the possibility that the endogenous opioid response does contribute to nicotine reinforcement but only as a delimited component of the neuroregulatory cascade of nicotine; and (e) the possibility that opioids contribute primarily to nicotine reinforcement under special conditions such as stress. Taking these considerations into account should allow studies on endogenous opioid effects to begin to do justice to the complexity of both smoking behavior and the actions of nicotine.

Inherited, selective hyporesponsiveness to the analgesic action of nicotine in mice.

The acute dose-dependent analgesic activity of nicotine, as measured by the tail-flick assay, differed significantly between CD-1 and CF-1 outbred strains of mice. Differing responsiveness to the tail-flick stimulus did not explain this pharmacological effect. The inherent analgesic hyporesponsiveness of CF-1 mice was pharmacologically selective. Xilocaine and morphine produced an analgesic response of large magnitude in CF-1 mice. Reduced efficacy of nicotine in the CF-1 analgesia assay was not observed in its action on locomotor activity or in the induction of seizures and lethality. These findings have practical significance in identifying the importance of genotype in choice of strain for preclinical pharmacological studies of nicotine-induced analgesia and indicate that genetic analysis may provide a valuable tool for investigating the mechanism underlying the analgesic action of nicotine.