Tobacco dependence dramatically increases health burdens and financial costs. Limitations of current smoking cessation therapies indicate the need for improved molecular targets. Nicotine, the main addictive component of tobacco, exerts its dependency effects via nicotinic acetylcholine receptors (nAChRs). The homomeric α7 nAChR is one of the most abundant receptors found in the brain and has unique features in comparison to other nAChR subtypes such as high calcium permeability, low probability of channel opening, and a rapid desensitization rate. α7 nAChR agonists reduce nicotine's rewarding properties in the conditioned place preference (CPP) test and i.v. self-administration. Recently, the peroxisome proliferator-activated receptor type-α (PPARα) has been implicated as a downstream signaling target of the α7 nAChR in ventral tegmental area dopamine cells. It is unknown whether the intrinsic characteristics of the α7 nAChR and PPARα are involved in its attenuation of nicotine reward. Therefore, this dissertation sought to investigate the role of α7 nAChRs in a mouse model of nicotine CPP and nicotine withdrawal by 1) investigating the impact of pharmacological modulation of α7 nAChR function in nicotine dependence and 2) evaluating a possible role for PPARα as a downstream mediator of α7 nAChRs in nicotine dependence. Positive allosteric modulators (PAMs) and a silent agonist were used to investigate the role of α7 nAChR conformations. The utilization of the α7 nAChR Type I PAM NS1738, Type II PAM PNU120596, and silent agonist NS6740 provided insight about the probability of channel opening (NS1738, PNU120596), desensitization (PNU120596, NS6740), and modulation of the endogenous acetylcholine/ choline tone (NS1738, PNU120596) as it relates to the α7 nAChR in nicotine CPP and withdrawal. In addition, this dissertation sought to elucidate the role of the α7 nAChR and PPARα in nicotine dependence using pharmacological interventions. The results suggest that the role of the α7 nAChR in nicotine dependence is conformation-dependent and PPARα-mediated. This dissertation is the first to report PPARα-mediation of the effects of α7 nAChR in nicotine reward and attenuation of nicotine withdrawal signs by PPARα activation. This data supports the development of α7 nAChR agonists and PPARα activators as possible smoking cessation aids.

Orientador: Ercy Mara Cipulo Ramos / Banca: Dionei Doffinger Ramos / Banca: Mariangela Macchione / Resumo: Introdução: A exposição ao cigarro promove alterações que prejudicam a eficácia do transporte mucociliar. Contudo, a influência da intensidade de exposição, assim como os efeitos da abstinência ao tabagismo sobre essas alterações foram pouco elucidados. Objetivos: Avaliar a influência de diferentes intensidades de exposição ao cigarro sobre o transporte mucociliar e o efeito da cessação do tabagismo sobre o transporte mucociliar nasal em fumantes avaliados durante um período de 180 dias. Casuística e Métodos: Participantes de um programa de cessação ao tabagismo, foram avaliados quanto ao histórico tabagístico, ao nível de dependência à nicotina, à avaliação da função pulmonar (espirometria), a concentração de monóxido de carbono no ar exalado (COex), ao nível de carboxihemoglobina (COHb) e ao transporte mucociliar (tempo de trânsito de sacarina - TTS). Para comparação foi avaliado um grupo... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction: Exposure to cigarette smoke promotes changes that harm the effectiveness of the mucociliary clearance. However, the influence of the intensity of exposure, as well as the effects of abstinence from smoking on these changes is poorly understood. Objectives: To assess the influence of different intensities of exposure to cigarette smoke on mucociliary clearance and the effect of cessation of smoking on nasal mucociliary clearance in smokers evaluated over a period of 180 days. Methods: Participants from a smoking cessation programme, were evaluated about smoking behavior, level of nicotine dependence, lung function (spirometry), the carbon monoxide in exhaled air (exhaled CO), the carboxyhemoglobin (COHb) and mucociliary clearance (saccharin transit time - STT). Was evaluated for comparison... (Complete abstract click electronic access below) / Mestre

Made available in DSpace on 2014-06-11T19:22:49Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-12-14Bitstream added on 2014-06-13T20:47:32Z : No. of bitstreams: 1 xavier_rf_me_prud.pdf: 788260 bytes, checksum: 7ab87eb37bf3e7b481df9e653a6f0f74 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Introdução: A exposição ao cigarro promove alterações que prejudicam a eficácia do transporte mucociliar. Contudo, a influência da intensidade de exposição, assim como os efeitos da abstinência ao tabagismo sobre essas alterações foram pouco elucidados. Objetivos: Avaliar a influência de diferentes intensidades de exposição ao cigarro sobre o transporte mucociliar e o efeito da cessação do tabagismo sobre o transporte mucociliar nasal em fumantes avaliados durante um período de 180 dias. Casuística e Métodos: Participantes de um programa de cessação ao tabagismo, foram avaliados quanto ao histórico tabagístico, ao nível de dependência à nicotina, à avaliação da função pulmonar (espirometria), a concentração de monóxido de carbono no ar exalado (COex), ao nível de carboxihemoglobina (COHb) e ao transporte mucociliar (tempo de trânsito de sacarina – TTS). Para comparação foi avaliado um grupo... / Introduction: Exposure to cigarette smoke promotes changes that harm the effectiveness of the mucociliary clearance. However, the influence of the intensity of exposure, as well as the effects of abstinence from smoking on these changes is poorly understood. Objectives: To assess the influence of different intensities of exposure to cigarette smoke on mucociliary clearance and the effect of cessation of smoking on nasal mucociliary clearance in smokers evaluated over a period of 180 days. Methods: Participants from a smoking cessation programme, were evaluated about smoking behavior, level of nicotine dependence, lung function (spirometry), the carbon monoxide in exhaled air (exhaled CO), the carboxyhemoglobin (COHb) and mucociliary clearance (saccharin transit time - STT). Was evaluated for comparison... (Complete abstract click electronic access below)

Negative affect plays a critical role in nicotine dependence. Smokers report feeling that negative affect is a primary motivation to keep smoking. This study examined the relationship between individual differences in emotional experience, in particular emotional clarity and differentiation (individuals' ability to understand, describe, and differentiate between emotions), and smoking motivation. We hypothesized that emotional clarity would be related to affect, craving, and smoking satisfaction. A second goal was to test the ability of an emotional-labeling intervention to reduce negative affect and smoking motivation resulting from a negative emotion induction. We also tested whether emotional clarity moderated the effect of the negative affect manipulation upon smoking-related variables. We hypothesized that emotional clarity would moderate the effect of the emotional-labeling manipulation upon affect, craving, and smoking satisfaction. A correlational and two-group between-subjects design was used. Participants (170 participants; 86 males) first completed baseline measures, then received a mood induction (via video). They then were randomized to one of two conditions (emotion labeling and writing control). Results indicate that emotional clarity was related to affect, craving, and smoking satisfaction ratings, such as those higher on emotional clarity reported more positive affect, less cravings, and having experienced aversive effects after smoking. We found no effect of the emotional labeling task. Although we replicated findings from previous studies showing a relationship between emotional clarity and mood, this study is the first to establish such a relationship with craving for a cigarette and aspects of smoking satisfaction.

Although cigarette smoke has been implicated in a causal relationship with various types of cancers, around 62% of all cancer patients are current smokers, recent quitters, or former smokers. While most patients who are smokers are motivated to quit after cancer diagnosis, 25 -30% of these patients continue to smoke. Furthermore, most quitters relapse after 2-3 years of post-chemotherapy. This represents a major health concern since several clinical studies revealed that perpetuation of smoking in cancer populations attenuates patient's well-being and quality of life. Smoking may impair healing, attenuate the efficacy of chemotherapy, increase the disease complications and diminish survival rates. However, the factors that involved in nicotine dependence in cancer patients are poorly understood. xii According to human research, it was suggested that tumor site, impact of cancer therapy and disease prognosis could be responsible of continuation of tobacco smoking among cancer patients and survivors. Recently, chemotherapy was shown to cause emotional deficits in humans (anxiety, insomnia and depression) and animals. In this project, we focused on the chemotherapeutic agent, paclitaxel, because it is widely used to treat solid tumors such as lung, head, neck and breast cancer. We previously reported that paclitaxel induced general affective deficits in mice such as anhedonia, anxiety and depression-like behaviors. We therefore hypothesized that the chemotherapeutic agent, paclitaxel may alter the rewarding and withdrawal properties of nicotine. We investigated the impact of paclitaxel on spontaneous nicotine withdrawal and nicotine reward in C57BL/6J mice by using variety of behavioral tests. Our findings showed that paclitaxel worsened the somatic and affective signs of nicotine withdrawal in male mice as well as attenuated of nicotine reward in the CPP assay. These behavioral changes were not due to an impact of nicotine metabolism by paclitaxel. Overall, paclitaxel changed the behaviors during nicotine withdrawal and reward and that suggested changing in the smoking behavior after exposure to chemotherapy.

Nicotine's rewarding effects are mediated through distinct subunits of nAChRs, encoded by different nicotinic cholinergic receptor (CHRN) genes and expressed in discrete regions in the brain. In the present study, we aimed to test the associations between rare variants at CHRN genes and nicotine dependence (ND), and alcohol dependence (AD). A total of 26,498 subjects with nine different neuropsychiatric disorders in 15 independent cohorts, which were genotyped on Illumina, Affymetrix, or PERLEGEN microarray platforms, were analyzed. Associations between rare variants (minor allele frequency (MAF) <0.05) at CHRN genes and nicotine dependence, and alcohol dependence were tested. The mRNA expression of all Chrn genes in whole mouse brain and 10 specific brain areas was investigated. All CHRN genes except the muscle-type CHRNB1, including eight genomic regions containing 11 neuronal CHRN genes and three genomic regions containing four muscle-type CHRN genes, were significantly associated with ND, and/or AD. All of these genes were expressed in the mouse brain. We conclude that CHRNs are associated with ND (mainly) and AD, supporting the hypothesis that the full catalog of ND/AD risk genes may contain most neuronal nAChRs-encoding genes.

No description available.

O tabagismo é um problema de saúde pública em todo o mundo. Entre as mulheres, devido ao aumento da prevalência comparada aos homens, o tabagismo feminino tem merecido atenção. Para o enfrentamento, é necessário entender o fenômeno e criar estratégias mais adequadas que incluam aspectos emocionais e sociais da dependência do tabagismo. Este estudo buscou descrever os esquemas cognitivos, sintomas de ansiedade e depressão de 112 mulheres que procuraram tratamento para cessação do tabagismo e sua relação com o insucesso do tratamento. A coleta de dados incluiu roteiro de entrevista estruturada e escalas validadas para a população brasileira que têm o objetivo de avaliar os esquemas cognitivos, sintomas de ansiedade e de depressão, e aspectos da dependência do cigarro. O conhecimento de fatores emocionais envolvidos no tabagismo e sua cessação podem ser úteis às ações de apoio à mudança comportamental do fumante. Objetivo: Descrever o perfil psicológico de mulheres que buscam cessação do tabagismo quanto aos esquemas cognitivos, sintomas de ansiedade e depressão antes e depois do tratamento com Terapia Cognitivo- Comportamental em grupo, e analisar fatores que contribuem para o desfecho de cessação. O desenho do estudo foi longitudinal e transversal. Para avaliar os esquemas cognitivos, o Questionário de Esquemas de Young em sua forma curta foi utilizado. Os grupos de terapia cognitivo-comportamental foram realizados concomitantes ao cuidado usual por médicos do estudo. Esses profissionais foram treinados no protocolo do estudo e o seguimento foi realizado por telefone por um membro do estudo independente e cego. Resultados: Os resultados forneceram evidências de que esquemas cognitivos tiveram relação significativa com os sintomas de depressão e ansiedade, com a adesão e os resultados do tratamento (cessação do tabagismo) / Cigarette smoking is a major public health problem worldwide. Among women, due to increased prevalence compared to men, the female smoking has deserved attention. To face, it is necessary to understand the phenomenon and create more appropriate strategies that include emotional and social aspects of smoking dependence. This study aimed to describe the cognitive schemes, symptoms of anxiety and depression of 112 women who sought treatment for smoking cessation and its relationship to treatment failure. Data collection included structured interview and validated scales for the Brazilian population who have to evaluate the cognitive schemes, symptoms of anxiety and depression and aspects of tobacco dependence. Knowledge of emotional factors involved in smoking and its cessation may be helpful to actions to support behavioral change of the smoker. Objective: To describe the psychological profile of women seeking smoking cessation regarding cognitive schemes, symptoms of anxiety and depression before and after treatment with cognitive-behavioral therapy in groups and analyze factors that contribute to the outcome of cessation . Method: The layout of the study was longitudinal and transversal. To assess the cognitive schemes, the Young Schema Questionnaire in its short form was used. The Cognitive Behavioral Therapy groups were conducted at the same time as the medical care and were applied by psychologists and medical doctors. These professionals were trained in the study protocol and the follow-up was conducted by telephone by the same independent and blind evaluator. Results: Our results provided evidence that the cognitive schemas of those women who sought treatment for quitting smoking showed a significant relation to the symptoms of depression and anxiety, with the adherence and the results of the treatment (quitting smoking), and with the positive impact of Cognitive Behavioral Therapy in decreasing schemas scores. It was also evident that the overall time throughout which the individual had smoked correlated to smaller rates of being able to quit smoking

The college setting represents an untapped window of opportunity to target the growing number of college student smokers. To address this need the current study tested an intervention drawing upon research from social psychology and previously effective health-related interventions. The primary purpose of this study was to examine the efficacy of an experiential, dissonance-enhancing smoking intervention for increasing motivation to quit smoking and reducing smoking by comparing it to two control groups, in a three-arm randomized study. Participants were 215 college student smokers randomized to an experiential smoking intervention, a traditional educational smoking intervention, or an experiential intervention on nutrition. A secondary purpose of the present study was to explore the influence of possible mediating variables (e.g. risk perceptions, smoking knowledge) and to investigate whether demographic or smoking history variables would moderate the effects of the intervention. As predicted, the experiential smoking intervention was more effective in increasing motivation to quit as compared to both groups. However, moderator analyses revealed that the effect was found only for females. Increased motivation to quit was also demonstrated on an immediate behavioral measure of impact. Additional analyses indicated that a greater reduction in smoking and higher quit rates at follow-up were found for participants in both smoking conditions as compared to participants in the Nutrition control condition. Potential mechanisms of change were not supported; however, participants who received the experiential smoking intervention exhibited greater smoking knowledge and were more likely to report greater negative consequences of smoking. Findings support the efficacy of a standard didactic intervention, and the added efficacy of a more intensive experiential intervention. Implications for intervention are discussed.

This paper describes the distribution of dependence criteria and diagnoses in a sample of 14- to 24-year-olds from Munich, Germany (n = 3,021; 71% response rate), evaluates differences between nondependent and dependent smokers and examines associations of smoking with other substances, affective and anxiety disorders. Assessment was made using the M-CIDI. The lifetime prevalence of DSM-IV nicotine dependence in the total sample is 19%, rising to 52% among regular smokers. No gender differences were seen in the progression from regular smoking to nicotine dependence, although men were more likely than women to initiate regular use. Analysis of daily cigarette use identified a significant dose-response relationship with the number of endorsed DSM-IV dependence criteria with unsuccessful cut-backs being the most prevalent criterion. As compared to nondependent smokers, dependent smokers were more likely to associate negative health effects with smoking and to have a desire to change and attempt a change in their pattern of use. Regular use of nicotine was found to be significantly associated with other substance and nonsubstance disorders, although dependent regular use was more strongly associated with these disorders than nondependent regular use. These results indicate that daily smoking is a behavior which is resistant to change despite an expressed desire and repeated cut-back attempts. Although initiation of regular smoking among nonsmokers does not occur frequently after the early twenties, the risk for dependent smoking among regular users persists into adulthood and is associated with a range of mental disorders.