The role of α7-nicotinic acetylcholine receptor in a rat model of chronic nicotine-induced mechanical hypersensitivity.

Smokers have a higher incidence of chronic pain than non-smokers, but the neural mechanism is not yet fully understood. Nicotine is the main component of tobacco and acts as an agonist for nicotinic cholinergic receptors (nAChRs) in the nervous system. This study was approved by the IACUC of UM. The effects of chronic nicotine administration on mechanical sensitivity were studied using a rat model. The changes in the expression levels of the α7 isoform of nAChR (α7-nAChR), inflammatory cytokines TNFα and COX-2, as well as the density of neuro-immune cells (astrocytes and microglia) were measured concurrently. The results indicate that long-term nicotine administration induces hypersensitivity to mechanical stimuli, as demonstrated by a significant reduction in the pain perception threshold. In response to nicotine, the expression levels of α7-nAChR increased in the periaqueductal gray matter (PAG) and decreased in the spinal cord. Acute administration of the selective α7-nAChR agonist CDP-Choline reversed this hypersensitivity. Chronic nicotine administration led to an increase of microglial cells in the dorsal horn of the spinal cord and increased expression levels of the cytokines TNFα and COX-2. This study suggests that decreased α7-nAChR expression in the spinal cord, as a result of long-term exposure to nicotine, may be causatively linked to chronic pain. Simultaneously, the increase of neuro-immune factors in the spinal cord is also a potential factor leading to chronic pain.

Varenicline aggravates atherosclerotic plaque formation in nicotine-pretreated ApoE knockout mice due to enhanced oxLDL uptake by macrophages through downregulation of ABCA1 and ABCG1 expression.

Varenicline is a widely used and effective drug for smoking cessation. We previously reported that varenicline aggravates atherosclerosis in apolipoprotein E knockout (ApoE KO) mice. However, it remains unknown whether varenicline affects cardiovascular events in patients with nicotine addiction. Here, we examined the effect of varenicline on atherosclerotic plaque formation in nicotine-pretreated ApoE KO mice and oxidized low-density lipoprotein (oxLDL) uptake in nicotine-treated peritoneal macrophages. Varenicline caused significant progression of plaque formation in the whole aorta and aortic root and further accelerated the increased formation of a macrophage-rich plaque area in the aortic root in nicotine-pretreated ApoE KO mice. Varenicline (10 µM) enhanced oxLDL uptake in peritoneal macrophages. Furthermore, this treatment significantly further lowered the decreased protein levels of ATP-binding cassette (ABC) transporter without affecting the expression of scavenger receptors LOX-1 and CD36 in RAW264.7 cells treated with 100 nM nicotine. Varenicline enhanced nicotine-induced oxLDL uptake in macrophages through decreased expression of cholesterol efflux transporters ABCA1 and ABCG1 and thereby progressed atherosclerotic plaque formation. Taken together, we tentatively conclude that nicotine exposure before and/or during varenicline treatment can aggravate varenicline-increased atherosclerotic plaque formation and progression. Therefore, this enhanced risk requires special consideration when prescribing varenicline to smoker patients.

Synthesis of Novel Nicotinic Ligands with Multimodal Action: Targeting Acetylcholine α4ß2, Dopamine and Serotonin Transporters.

Nicotinic acetylcholine receptors (nAChRs), serotonin transporters (SERT) and dopamine transporters (DAT) represent targets for the development of novel nicotinic derivatives acting as multiligands associated with different health conditions, such as depressive, anxiety and addiction disorders. In the present work, a series of functionalized esters structurally related to acetylcholine and nicotine were synthesized and pharmacologically assayed with respect to these targets. The synthesized compounds were studied in radioligand binding assays at α4ß2 nAChR, h-SERT and h-DAT. SERT experiments showed not radioligand [3H]-paroxetine displacement, but rather an increase in the radioligand binding percentage at the central binding site was observed. Compound 20 showed Ki values of 1.008 ± 0.230 µM for h-DAT and 0.031 ± 0.006 µM for α4ß2 nAChR, and [3H]-paroxetine binding of 191.50% in h-SERT displacement studies, being the only compound displaying triple affinity. Compound 21 displayed Ki values of 0.113 ± 0.037 µM for α4ß2 nAChR and 0.075 ± 0.009 µM for h-DAT acting as a dual ligand. Molecular docking studies on homology models of α4ß2 nAChR, h-DAT and h-SERT suggested potential interactions among the compounds and agonist binding site at the α4/ß2 subunit interfaces of α4ß2 nAChR, central binding site of h-DAT and allosteric modulator effect in h-SERT.

7-Azaindole Analogues as Bioactive Agents and Recent Results.

Azaindoles have been accepted as important structures having various biological activities in medicinal chemistry in novel drug discovery. Various azaindole derivatives have been used commercially and newer analogues are synthesized continuously. As in literature, azaindole is a very potent moiety, its derivatives displayed a number of biological activities such as kinase inhibitors, cytotoxic agents, anti-angiogenic activity, CRTh2 receptor antagonists, melanin agonists, nicotine agonists, effectiveness in alzheimer disease, cytokinin analogs, Orai inhibitors in asthma and chemokine receptor- 2 (CCR2) antagonists. This review consists of biological activities of various azaindole analogs, reported so far, and their structure activity relations, along with future perspectives in this field.

Nicotine Metabolism-informed Care for Smoking Cessation: A Pilot Precision RCT.

Introduction: Varenicline doubles cessation over nicotine replacement therapy (NRT) patch for "normal," but not "slow," nicotine metabolizers, as assessed by the nicotine metabolite ratio (NMR). Metabolism-informed care (MIC) could improve outcomes by matching normal metabolizers with non-nicotine medication (e.g., varenicline) and slow metabolizers with NRT patch. Methods: We conducted a feasibility randomized controlled trial of MIC versus guideline based care (GBC) among 81 outpatient adult daily smokers with medical comorbidity. Participants reported perceptions of MIC, underwent blood draw for NMR, and received expert cessation counseling. For MIC participants, medication selection was informed by NMR result (normal (≥0.31) vs. slow (< 0.31)). The primary outcome was MIC feasibility, reflected by attitudes toward MIC and by match rates between NMR and medication. Secondary endpoints (cessation confidence, medication use, smoking status) were assessed over 6 months to inform future studies. Results: Participants were median age 53 years, 46% female, 28% black, and ~90% endorsed MIC. Despite high varenicline prescription rates (~60%) in both arms, NMR-medication matching was higher in MIC (84%) versus GBC (58%) participants (p=0.02); unadjusted odds ratio (OR) 3.67, 95% confidence interval [1.33, 11.00; p-value=0.02]. Secondary endpoints were similar at 1, 3, and 6 months. Conclusions: MIC, an NMR-based precision approach to smoking cessation, was acceptable to 90% of smokers and improved NMR-medication match rates more than 3-fold compared to GBC, even with generally high use of varenicline. These data support the feasibility of MIC, which could maximize efficacy of smoking cessation medication while minimizing side effects and cost. Implications: Among treatment-seeking daily smokers with medical comorbidity, most viewed metabolism-informed care (MIC), guided by the nicotine metabolism ratio (NMR), favorably, and were willing to accept MIC-guided medication. Compared to GBC participants (58%), more MIC participants (84%) were prescribed NMR-matched medication (i.e., normal metabolizers received varenicline; slow metabolizers received NRT patch). MIC increased the odds of optimized matching between NMR and medication more than 3-fold over GBC. Because the number needed to treat (NNT) to help one normal metabolizer quit smoking is only 4.9 for varenicline versus 26 for patch, broad implementation of MIC will improve drug efficacy in normal metabolizers as well as minimize side effects in slow metabolizers.

Marrow stem cell differentiation for valvulogenesis via oscillatory flow and nicotine agonists: unusual suspects?

Fluid-induced oscillatory shear stress (OSS) and nicotine are known antagonists in cardiovascular disease. However, from a regenerative medicine standpoint, we hypothesized that these parameters may support the cell differentiation of bone marrow mesenchymal stem cells (BMMSCs) for engineering heart valves. In this study, OSS and nicotine (10-6M) were applied individually to BMMSCs in monolayer culture. In both cases, a significantly higher expression of CD31 was detected compared to corresponding controls (p<0.05). We interpret our findings to indicate that both OSS and nicotine independently support mesenchymal to endothelial transformation; however, the underlying mechanism for this transformation in terms of the cell cytoskeletal structure was entirely different between the two stimulants. In the case of OSS, F-actin filaments exhibited a stretching response and formed a preferential alignment with each other. However, in the nicotine-treated group, a clear increase was observed in the number of actin filaments present, which led to the maximum expression of CD31 in comparison to the OSS and control groups. From our findings, we speculate that while nicotine may stimulate an increase in the differentiation of BMMSCs to endothelial cells, OSS may play a greater role in cellular distribution and the eventual creation of a tissue engineered heart valve (TEHV) endothelium.

Dejar de fumar con reducción progresiva / Quit smoking with progressive reduction

No disponible

Anhedonia as a component of the tobacco withdrawal syndrome.

Animal research suggests that anhedonia is a tobacco withdrawal symptom, but this topic has not been addressed definitively in research with humans. This research sought to determine whether anhedonia is (a) an element of the tobacco withdrawal syndrome in humans and (b) an impediment to successful tobacco cessation. Data were from 1,175 smokers (58.3% women; 85.5% White) participating in a randomized double-blind, placebo-controlled trial of smoking cessation pharmacotherapies. Ecological momentary assessments for 5 days before and 10 days after the target quit day were used to assess anhedonia and other established withdrawal symptoms. Consistent with drug withdrawal, anhedonia showed an inverted-U pattern of change in response to tobacco cessation and was associated with the severity of other withdrawal symptoms and tobacco dependence. Postquit anhedonia was associated with decreased latency to relapse (hazard ratio = 1.09, 95% confidence interval [CI] [1.02, 1.17]) and with lower 8-week point-prevalence abstinence (odds ratio = .91, 95% CI [.86, .97])-relations that remained significant when other withdrawal symptoms were included as predictors. Finally, nicotine replacement therapy nearly fully suppressed the increase in abstinence-related anhedonia (ß = -.66, p < .001), suggesting agonist suppression of withdrawal. Results suggest that anhedonia is a unique and motivationally significant element of the tobacco withdrawal syndrome in humans. These results have implications for defining and assessing tobacco use disorder and for understanding and treating tobacco addiction.

El tabaco de liar / Roll your own tobacco

El consumo de tabaco de liar (TL) está incrementando en la población general en los últimos años. El principal objetivo de nuestro estudio es analizar las características socio-demográficas y de tabaquismo de un grupo de fumadores de TL que han acudido a nuestra Unidad para dejar de fumar. Presentamos, además, los datos de eficacia y seguridad de uso de los distintos tratamientos en este grupo de fumadores. Hemos revisado las historias clínicas y de tabaquismo de un total de 62 sujetos (53% hombres, edad media 46,1 años) fumadores de TL. Comparamos los datos de estos fumadores con una muestra histórica de fumadores de tabaco manufacturado (TM) de nuestra Unidad, que está constituida por 59 sujetos (46% hombres, 51,6 años de edad media). Las principales diferencias que hemos encontrado entre ambos grupos han sido: los fumadores de TL tienen más altas concentraciones de CO en su aire espirado (27,9 vs. 21,48 ppm, p menor de 0,05) que los fumadores de TM a pesar de que estos consumen un mayor número de cigarrillos diarios (18,5 vs. 27,9 CPD, p< 0,05). Igualmente encontramos que los niveles de cotinina en sangre en los fumadores de TM son más altos que los de los de TL (396,38 vs. 334,38 ng/ml, p< 0,05). La tasa de abstinencia a los seis meses de seguimiento fue de 59,6% para los consumidores de TL y de 55,17% para los de TM. En conclusión, los fumadores de TL tienen más altas concentraciones de CO a pesar de que fuman un menor número de cigarrillos diarios y los tratamientos para dejar de fumar se muestran muy eficaces en este grupo de fumadores (AU)

Rolling tobacco consumption has increased in recent year. The primary objective of the study is to analyze the sociodemographic and smoking characteristics in a group of rolling tobacco smokers who come to our unit to give up smoking. We also present the efficacy and safety data from different treatments in this group. We have examined the clinic and tobacco histories on a total of 62 rolling tobacco smokers (53% males average age 46.1) and we have compared this data with a historical sample of conventional tobacco smokers in our unit, this group consists of 59 smokers (46% males, average age 51.6) The main differences between both groups were: rolling tobacco smokers have higher CO concentrations in the exhaled air (27.9 v. 1.48 ppm, p< 0.05) compared to the conventional tobacco smokers though they smoke fewer cigarettes per day (18.5 v. 334.38 ng/ ml, p< 0.05). The higher abstinence rate at 6 month in these both group were 59,6% (rolling tobacco smokers) and 55,17% (conventional tobacco smokers). In conclusion, rolling tobacco smokers have higher CO concentrations in the exhaled air even though they smoke fewer cigarettes per day. The cessation treatment is very effective in this group of smokers (AU)

Agonistas parciais dos receptores de nicotina para a cessação do tabagismo / Partial agonists nicotine for smoking cessation

Introdução: Os agonistas parciais dos receptores de nicotina podem ajudar as pessoas a deixar de fumar por meio da manutenção de níveis moderados de dopamina para contrabalançar os sintomas de abstinência (atuando como agonistas) e da redução da satisfação de fumar (agindo como antagonistas).Objetivos: Avaliar a eficácia e a tolerabilidade dos agonistas parciais do receptor de nicotina, incluindo citisina, dianiclina e vareniclina para cessação do tabagismo.Métodos de busca: Foram realizadas buscas por estudos no Cochrane Tobacco Addiction Group?s Specialised Register utilizando-se os termos ?cytisine? or ?Tabex? or ?dianicline? or ?varenicline? or ?nicotine receptor partial agonist? no título, no resumo, ou como palavras-chave. Este registro especializado é formado a partir de pesquisas no Medline, Embase, PsycINFO e Web of Science usando termos MeSH e texto livre para identificar ensaios clínicos controlados de intervenções para cessaçãoe prevenção do tabagismo. Os autores entraram em contato com os autores dos estudos para obter informações complementares, se necessário. A atualização mais recente deste registro especializado foi em dezembro de 2011. Os autores também procuraram em bases online de registros de ensaios clínicos.Critérios de seleção: Foram incluídos ensaios clínicos randomizados que compararam as medicações listadas acima com placebo, bupropiona e adesivos de nicotina. Foram excluídos estudos que não relataram um período de acompanhamento mínimo de seis meses a partir do início do tratamento.Coleta de dados e análise: Foram extraídos os dados sobre tipo de participante, dose e duração do tratamento, medidas de resultados,procedimento de randomização, ocultação de alocação e acompanhamento. O desfecho principal foi a abstinência do fumo durante o acompanhamento. . .. .

Vareniclina en el tratamiento del tabaquismo: eficacia y seguridad en población general, psiquiátrica y drogodependiente / No disponible

Desde el año 2006 la vareniclina se está utilizando como tratamiento de primera elección para dejar de fumar. La mayoría de estudios publicados sobre eficacia y seguridad de este producto se han hecho sobre muestras de fumadores sanos. El presente trabajo es una revisión de estudios publicados que aportan datos sobre eficacia y seguridad de vareniclina en tres tipos de población: población general, psiquiátrica y drogodependiente. En población general se presentan los resultados sobre eficacia en comparación a placebo, Terapia Sustitutiva de Nicotina y Bupropion. Se valoran los estudios relacionados con la seguridad que tratan sobre los efectos adversos psiquiátricos de la medicación. En población psiquiátrica y población drogodependiente se valoran las conclusiones de los pocos estudios relacionados con el tema. Se concluye que la eficacia y la seguridad de vareniclina en población general están confirmadas. Destaca la escasez de estudios controlados realizados con población psiquiátrica y drogodependiente. Se recomienda monitorizar bien los pacientes psiquiátricos y drogodependientes que tomen este fármaco (AU)

Varenicline has been used as a first-line treatment for smoking cessation since 2006, but most studies to date on its effi cacy and safety have been conducted in samples of healthy smokers. This paper reviews published studies about the efficacy and safety of varenicline in three types of population: the general population, psychiatric patients and drug addicts. In the general population we present the results of efficacy of varenicline compared to placebo, nicotine replacement therapy and bupropion. Results about neuropsychiatric adverse events are also presented. In psychiatric patients and drug-dependent population we present the conclusions of the few studies on the topic. Our findings confi rmed the effi cacy of varenicline in the general population and emphasize the paucity of controlled studies in psychiatric and drug addict populations. We thus recommend that treatment should be monitored in these latter populations (AU)

Action of nicotine and analogs on acetylcholine receptors having mutations of transmitter-binding site residue αG153.

A primary target for nicotine is the acetylcholine receptor channel (AChR). Some of the ability of nicotine to activate differentially AChR subtypes has been traced to a transmitter-binding site amino acid that is glycine in lower affinity and lysine in higher affinity AChRs. We studied the effects of mutations of this residue (αG153) in neuromuscular AChRs activated by nicotine and eight other agonists including nornicotine and anabasine. All of the mutations increased the unliganded gating equilibrium constant. The affinity of the resting receptor (K(d)) and the net binding energy from the agonist for gating (ΔG(B)) were estimated by cross-concentration fitting of single-channel currents. In all but one of the agonist/mutant combinations there was a moderate decrease in K(d) and essentially no change in ΔG(B). The exceptional case was nicotine plus lysine, which showed a large, >8,000-fold decrease in K(d) but no change in ΔG(B). The extraordinary specificity of this combination leads us to speculate that AChRs with a lysine at position αG153 may be exposed to a nicotine-like compound in vivo.

[Safety of nicotine addiction treatment]. / Bezpieczenstwo terapii uzaleznien od nikotyny.

Not all smoking addicts can succeed in quitting smoking with willpower only. These people may use nicotine replacement therapy (patches, gums, lozenges, sublingual tablets, inhalers), medicines (bupropion, varenicline and cytisine) and psychological aid. Each drug, besides its therapeutic effect, creates the risk of adverse reactions which number and severity is not always accepted by the patient. The aim of the study was to analyze adverse effects of bupropion, varenicline and cytisine formulations reported by patients. From July 2011 to June 2013 Regional Centre for Monitoring Adverse Drug Reactions (Department of Clinical Pharmacology, Department of Cardiology, Poznan University of Medical Sciences) recorded 32 suspected adverse reactions to the use of drugs for the treatment of nicotine addiction (12 after the preparation of cytisine and varenicline, 8 after preparations of bupropion). High determination caused that none of the patients withdrew from the therapy because of adverse effects.

Nicotina y modelos animales: ¿qué nos aporta el paradigma de enriquecimiento ambiental? / Nicotine and animal models: what does the environmental enrichment paradigm tell us?

El Enriquecimiento Ambiental (Environmental Enrichment o EE) es un modelo de alojamiento basada en la estimulación a nivel físico, cognitivo y sensorial de roedores. Esta condición se caracteriza por el alojamiento de un grupo de animales en cajas grandes que contienen distintos objetos como túneles, juguetes y ruedas de correr. El principal objetivo del presente trabajo es plantear los principales argumentos que sugieren que el alojamiento en condiciones de EE puede disminuir la vulnerabilidad a desarrollar adicción a la nicotina y a otras drogas de abuso, así como revisar estudios experimentales recientes relacionados con este área. Con este fin, se presenta una revisión de los principales cambios inducidos por el EE a nivel físico, neurobiológico y conductual y se exponen los resultados obtenidos en diversos estudios recientes que indican que el alojamiento en EE induce cambios neuroquímicos (potenciación del aumento de liberación de dopamina inducida por la nicotina en el córtex cerebral) y conductuales (mayor capacidad para discriminar la presencia de recompensa y disminución de la impulsividad) que apoyarían la hipótesis planteada. En base a estos resultados, cabría proponer el EE como un modelo adecuado para el estudio de la vulnerabilidad a la adicción a diferentes drogas de abuso como la cocaína o la nicotina aunque es necesario realizar más estudios que permitan establecerlas bases neurobiológicas de los efectos inducidos por la exposición a ambientes enriquecidos y su posible relación con modificaciones en los sistemas cerebrales de refuerzo(AU)

The Environmental Enrichment (EE) paradigm is a housing condition which aims is to provide physical, cognitive and sensorial stimulation to rodents. Animals are housed in larger cages containing in animate objects such as tunnels, toys and running wheels. The main aim of the current work is to tackle the arguments which suggest that EE may diminish vulnerability to developing addiction to nicotine and other drugs of abuse and to review recent experimental studies performed in relation to this subject. We discuss the major changes induced by EE at physical, neurobiological and behavioral levels and review the results of recent studies which indicate that EE promotes both neurochemical (potentiation of the increase in dopamine release induced by nicotine in the brain cortex) and behavioral changes (increased ability to discriminate the presence of reward and decreased impulsivity), thus supporting the hypothesis put forward. In light of these results, EE can be proposed as a model for the study of vulnerability to addiction to different drugs of abuse, including cocaine and nicotine, though further studies are needed in order to establish the neurobiological implications of the effects of exposure to enriched environments and their possible relationship with changes in brain reward systems(AU)

Use of an α3ß4 nicotinic acetylcholine receptor subunit concatamer to characterize ganglionic receptor subtypes with specific subunit composition reveals species-specific pharmacologic properties.

Drug development for nicotinic acetylcholine receptors (nAChR) is challenged by subtype diversity arising from variations in subunit composition. On-target activity for neuronal heteromeric receptors is typically associated with CNS receptors that contain α4 and other subunits, while off-target activity could be associated with ganglionic-type receptors containing α3ß4 binding sites and other subunits, including ß4, ß2, α5, or α3 as a structural subunit in the pentamer. Additional interest in α3 ß4 α5-containing receptors arises from genome-wide association studies linking these genes, and a single nucleotide polymorphism (SNP) in α5 in particular, to lung cancer and heavy smoking. While α3 and ß4 readily form receptors in expression system such as the Xenopus oocyte, since α5 is not required for function, simple co-expression approaches may under-represent α5-containing receptors. We used a concatamer of human α3 and ß4 subunits to form ligand-binding domains, and show that we can force the insertions of alternative structural subunits into the functional pentamers. These α3ß4 variants differ in sensitivity to ACh, nicotine, varenicline, and cytisine. Our data indicated lower efficacy for varenicline and cytisine than expected for ß4-containing receptors, based on previous studies of rodent receptors. We confirm that these therapeutically important α4 receptor partial agonists may present different autonomic-based side-effect profiles in humans than will be seen in rodent models, with varenicline being more potent for human than rat receptors and cytisine less potent. Our initial characterizations failed to find functional effects of the α5 SNP. However, our data validate this approach for further investigations.

Partial agonists for α4ß2 nicotinic receptors stimulate dopaminergic neuron firing with relatively enhanced maximal effects.

BACKGROUND AND PURPOSE: Partial agonists selective for α4ß2 nicotinic ACh receptors have been developed for smoking cessation as they induce weak activation of native α4ß2* receptors and inhibit effect of nicotine. However, it is unclear whether at brain functions there is an existence of receptor reserve that allows weak receptor activation to induce maximum physiological effects. We assessed the extent of α4ß2 partial agonist-induced increase of firing rate in dopaminergic neurons and evaluated the influence of receptor reserve. EXPERIMENTAL APPROACH: The relative maximal effects and potencies of six nicotinic agonists were assessed on recombinant human α4ß2 and α7 receptors expressed in mammalian cell lines by measuring calcium influx. Agonist-induced increase of the spontaneous firing rate of dopaminergic neurons was recorded using microelectrodes in the ventral tegmental area of rat brain slices. KEY RESULTS: All α4ß2 partial and full agonists increased the firing rate concentration-dependently. Their sensitivity to subtype-selective antagonists showed predominant activation of native α4ß2* receptors. However, partial agonists with relative maximal effects as low as 33% on α4ß2 receptors maximally increased the firing rate and induced additional depolarization block of firing, demonstrating that partial activation of receptors caused the maximum increase in firing rate in the presence of a receptor reserve. CONCLUSIONS AND IMPLICATIONS: Partial α4ß2 agonists induced relatively enhanced effects on the firing rate of dopaminergic neurons, and the effect was mainly attributed to the existence of native α4ß2* receptor reserve. The results have implications in the understanding of physiological effects and therapeutic efficacies of α4ß2 partial agonists.

Serotonin antagonists in the five-choice serial reaction time task and their interactions with nicotine.

Much research has implicated the serotonin (5-HT) system in cognitive functioning and psychomotor stimulant abuse, but its role depends on the subtypes of 5-HT receptors involved and the nature of the behavioural task. Here we aimed to extend previous studies by examining the role of 5-HT1A and 5-HT2C receptors in attentional performance. The effects of the selective 5-HT antagonists WAY-100635 and SB-242084 were assessed alone and for interactions with nicotine in the five-choice serial reaction time task in rats. The effects of several doses of WAY-100635 were tested in combination with a fixed dose of nicotine, and then various doses of nicotine were tested in combination with SB-242084. Systemic administration of WAY-100635 and SB-242084 induced opposing effects on speed-related measures in the five-choice serial reaction time task, with antagonism at 5-HT1A receptors increasing omission errors and response latency, and antagonism at 5-HT2C receptors reducing both omissions and latency, and also increasing anticipatory responses; neither drug affected accuracy. Nicotine itself improved all main indices of attention, and there was preliminary evidence that the detrimental effects of WAY-100635 on response latency were weakened by nicotine. Conversely, treatment with SB-242084 enhanced all speed-related indices of performance to above the levels seen under the influence of nicotine alone, thus suggesting that 5-HT2C antagonists might be useful to decrease reaction times if used as an add-on therapy to treat attentional decline.

Targeting nicotine addiction: the possibility of a therapeutic vaccine.

Cigarette smoking is the primary cause of lung cancer, cardiovascular diseases, reproductive disorders, and delayed wound healing all over the world. The goals of smoking cessation are both to reduce health risks and to improve quality of life. The development of novel and more effective medications for smoking cessation is crucial in the treatment of nicotine dependence. Currently, first-line smoking cessation therapies include nicotine replacement products and bupropion. The partial nicotinic receptor agonist, varenicline, has recently been approved by the US Food and Drug Administration (FDA) for smoking cessation. Clonidine and nortriptyline have demonstrated some efficacy, but side effects may limit their use to second-line treatment products. Other therapeutic drugs that are under development include rimonabant, mecamylamine, monoamine oxidase inhibitors, and dopamine D3 receptor antagonists. Nicotine vaccines are among newer products seeking approval from the FDA. Antidrug vaccines are irreversible, provide protection over years and need booster injections far beyond the critical phase of acute withdrawal symptoms. Interacting with the drug in the blood rather than with a receptor in the brain, the vaccines are free of side effects due to central interaction. For drugs like nicotine, which interacts with different types of receptors in many organs, this is a further advantage. Three anti-nicotine vaccines are today in an advanced stage of clinical evaluation. Results show that the efficiency of the vaccines is directly related to the antibody levels, a fact which will help to optimize the vaccine effect. The vaccines are expected to appear on the market between 2011 and 2012.

Pharmacological effects of nicotine on norepinephrine metabolism in rat brown adipose tissue: relevance to nicotinic therapies for smoking cessation.

In a two-year carcinogenicity study with administration of high doses of the partial nicotinic agonist varenicline (recently approved for smoking cessation), mediastinal hibernomas occurred in three male rats. To investigate potential mechanisms for partial and full nicotinic agonists to contribute to development of hibernomas, the effects of nicotine on rat brown adipose tissue (BAT) were studied. Male and female rats were administered nicotine at doses of 0, 0.3, and 1 mg/kg subcutaneously for fourteen days. Intrathoracic (mediastinal periaortic and mediastinal perithymic) BAT and interscapular BAT were examined microscopically, and determinations of uncoupling protein-1 (UCP-1) expression and norepinephrine (NE) content were made. Additionally, NE turnover was measured in mediastinal periaortic and perithymic BAT. Nicotine (1 mg/kg) administration resulted in decreased vacuolation only in mediastinal periaortic and mediastinal perithymic BAT of males and elevated UCP-1 in mediastinal periaortic BAT of males and females. Increased NE content occurred only in mediastinal periaortic BAT of males given 0.3 and 1 mg/kg doses, whereas NE turnover was decreased in both males and females given 1 mg/kg. Together, these data demonstrate that nicotine primarily affects mediastinal BAT in male rats, consistent with the gender and location of the hibernomas observed in the two-year carcinogenicity study.