This thesis was funded by the Department of Human Services (South Australia) to test the acceptability of nicotine patches to pregnant women and to assess the safety of nicotine patches for pregnant women, at least in terms of overall exposure to nicotine. The study was conducted in the antenatal clinics at the Women's and Children's Hospital, Adelaide and was a pilot for a planned larger study. If the pilot indicated that the nicotine patches could be used safely by this group of women, the larger study would examine the effectivemess of patches in a smoking cessation program. Four focus groups, three with pregnant women and one with their care providers, were used to elucidate issues for pregnant women related to smoking and the use of nicotine patches to aid cessation.

This thesis was funded by the Department of Human Services (South Australia) to test the acceptability of nicotine patches to pregnant women and to assess the safety of nicotine patches for pregnant women, at least in terms of overall exposure to nicotine. The study was conducted in the antenatal clinics at the Women's and Children's Hospital, Adelaide and was a pilot for a planned larger study. If the pilot indicated that the nicotine patches could be used safely by this group of women, the larger study would examine the effectivemess of patches in a smoking cessation program. Four focus groups, three with pregnant women and one with their care providers, were used to elucidate issues for pregnant women related to smoking and the use of nicotine patches to aid cessation.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 4 uppsatser.

The thesis topic bears the name: "Aspect of smoking among students of high medical schools". Smoking is one the most often appearing drug addictions nowadays in Europe. With reference to the World Health Organization, there are 1.3 billion of smoking people in the world today whereas consequences of smoking kill approximately 4.8 million of people every year, which are 560 people each hour. If the current trend continues, then in the current pace 10 million of people will die of the consequences of cigarette smoking during the year of 2020. Smoking invokes an enormous addiction to nicotine which bears itself considerable economic, social and health problems. There were some students from 1st and 4th grade of the present form of studies of all high medical schools selected. Those were students particularly from the schools: SZŠ and VOŠZ České Budějovice, SOŠZ and SOU Český Krumlov, SZŠ Jindřichův Hradec, SZŠ Tábor and SZŠ Písek. In total, 591 of students were responded whereas most of them were girls (87%). The average age of the responded ones was 17 years. The thesis consists of theoretical and empirical parts. The theoretical part deals with history of cigarette smoking, a definition of drug addiction, chemical composition of cigarette smoke and malignity of individual toxic elements. Further, there is a chapter concerning problem issues of electronic cigarette smoking in the theoretical part. In the conclusion of this part of the thesis, there are some statistical data referring to cigarette smoking stated. There are some findings of quite a few of authors dealing with problem issues of cigarette smoking and addiction to nicotine summarized here. The empirical part consists of findings from my own research analysis which was done with the intention to map the prevalence of smoking among future health workers and their opinion to cigarette smoking among healthcare staff and people preparing for their healthcare career. There are also the respondents' opinions and attitudes included. The aim of the thesis was: 1.: To find the prevalence of smoking of 1st and 4th grade of high medical schools students. 2.: To find what influence the respondents' surroundings have on the fact of their smoking. 3.: To find what attitude high medical school students have to healthcare staff smoking cigarettes. To reach the above mentioned aims, there were three hypotheses determined: H1: There is a statistically significant difference existing in the prevalence of smoking at 1st and 4th grade of high medical school students. H2: There is a statistically significant difference existing in the prevalence of cigarette smoking among students coming from families where at least one member smokes. H3: There are statistically significant differences in the attitude of 1st and 4th grade students to cigarette smoking among healthcare workers. To prove or disprove the mentioned hypotheses there is a method of quantitative research selected. A questionnaire was used to collect the data. The questionnaires including 23 questions were distributed among 591 students of high medical schools of the South Bohemia Region. Their rate of return was 85%. The collected data were processed in the form of transparent graphs and the hypotheses were statistically tested. Pursuant to the evaluation of respondents' answers including the statistical data testing were proved by the hypothesis which presumed that there were statistically significant differences in the prevalence of cigarette smoking 1st and 4th grade students. The difference really exists that the 4th grade students smoke more often. It is interesting that the most considerable difference is between the schools of SZŠ and VOŠZ České Budějovice. On the contrary, the percentage of smoking students of SOŠZ Český Krumlov in the 1st grade is considerably high. Hypothesis no. 2 was statistically proved as well. There is a real significant difference exist

La dépendance à la nicotine est un problème sociétal majeur. De nombreuses personnes continuent à fumer, malgré des conséquences négatives pour la santé bien connues. La recherche sur la toxicomanie se concentre généralement sur la motivation à obtenir cette drogue, le sevrage, rendu difficile par les symptômes de manque et la persistance des comportements appris. Au cours de cette thèse, je me suis concentrée sur les interactions entre les systèmes dopaminergique et nicotinique dans les comportements de prise de décision. Je me suis particulièrement intéressée aux effets de la nicotine administrée passivement de manière chronique. Mettre en évidence les modifications dans la signalisation dopaminergique, et les altérations des comportements de choix qu'implique la consommation de drogue, permet un autre éclairage sur l'état de dépendance, mais ouvre aussi de nouvelles perspectives sur le traitement des addictions et sur les notions de vulnérabilité et de comorbidité avec d'autres pathologies. Les théories de la prise de décision suggèrent que les individus analysent les bénéfices et les coûts potentiels pour guider leurs actions. Ainsi, faire des choix appropriés nécessite d'apprendre la valeur des options disponibles à partir de l'expérience. Ce processus reposerait principalement sur l'activité des neurones dopaminergiques. Une question cruciale est de savoir si les processus computationnels sous-jacents aux choix peuvent être modifiés de manière durable par l'exposition à la nicotine et/ou par la manipulation des récepteurs nicotiniques. Nous avons développé un paradigme comportemental, de type bandit manchot avec des stimulations intra-crâniales comme récompenses, qui permet d'évaluer la prise de décision basée sur la valeur et l'exploration. Nous avons étudié le rôle de la transmission nicotinique dans l'équilibre comportemental entre exploration et exploitation à l'aide de souris knock-out pour la sous-unité beta2 du récepteur nicotinique. Nous démontrons que les souris beta2KO explorent moins que les souris de type sauvage suggérant un rôle des nAChR dans la traduction de l'incertitude attendue en motivation à explorer. Dans une deuxième étape, nous analysons l'effet d'une exposition chronique à la nicotine sur ces processus de prise de décision. Il a été proposé que la libération phasique de dopamine serait cruciale pour l\'apprentissage, alors que l'activité tonique serait plus impliquée dans l'expression d'un comportement précédemment acquis. Nous montrons ici que la nicotine, sur le long terme, peut altérer l'activité spontanée des cellules dopaminergiques et ainsi modifier la libération phasique et tonique de dopamine. Cette modification se traduit par une augmentation de la "sensibilité à la valeur", et donc une altération des choix. Un individu sous nicotine chronique se concentre davantage sur les récompenses plus importantes. Nous avons mimé cet effet par une activation optogénétique tonique des neurones dopaminergiques. Ces travaux mettent en lumière les mécanismes qui sous-tendent les changements dans la prise de décision lors d'une exposition aux drogues. / Nicotine addiction is a major societal dilemma: despite the well-known adverse consequences to health, more than one billion persist in the habit. Much addiction research focuses on the motivation to obtain and take drugs and the difficulties of abstinence due to withdrawal effects and learned behaviour. My research focuses on the interactions between the dopaminergic and nicotinic systems in value-based decision-making behaviour, as well as the effects of passively administered nicotine within this framework. Understanding the alterations in the dopamine (DA) system and choice behaviour occurring with drug consumption provides another angle on the addictive state, the general predispositions and vulnerabilities for co morbid disorders. This knowledge could unveil new perspectives towards addiction treatment. Theories of decision-making suggest that individuals analyse potential benefits and costs to guide their actions based on experience. A multitude of studies have drawn links between DA cell activity and such choice behaviour. Dopamine signals attribute to the evaluation of available options to select future actions. The addictive nature of nicotine is well established, but can a much more alarming link be made between its effect on the DA system and fundamental perception of our environment ? Could basic computations underlying choices be significantly modified by drug exposure and/or by the manipulation of nicotinic receptors ? We designed a behavioural paradigm that allows us to assess value-based decision-making in different mouse models and with different manipulations of the cholinergic-dopaminergic circuits. We investigated the role of nicotinic transmission in the exploration/exploitation tradeoff using a beta2 subunit-containing nicotinic acetylcholine receptor knockout mouse model. Using a spatial version of a three-armed bandit task and intra-cranial self-stimulation as reward, we demonstrate that beta2KO mice explore less than the WT. This finding suggests the role of specific nAChRs in the translation of expected uncertainty into motivational value and exploratory decision-making. Secondly, we analysed the effect of chronic nicotine exposure in this decision process. It has been proposed that phasic dopamine release could provide a teaching signal necessary for learning, while tonic dopamine levels could influence the implementation of previously learned behaviours. Here we show that long-term nicotine exposure can alter the spontaneous activity of VTA DA cells and therefore change phasic and tonic DA signalling. These modifications translate into an enhanced value-sensitivity; the ability to discriminate between different values. We replicated this effect through optical stimulation of VTA DA neurons on a high tonic frequency. This illustrates that organisms under chronic nicotine focus on higher rewards. This data sheds a new light on the mechanisms underlying drug-induced changes in decision-making.

BACKGROUND: Tobacco is the most commonly used addictive substance among adolescents, according to the ESPAD study, and is often the first psychoactive substance to try out in life. However, the risks associated with the use of tobacco at the young age are not negligible. In the Ambulance for children and adolescents addictology Clinics of addictology, where attend adolescents with various addictological and psychological problems, no research regarding the use of nicotine has been carried out. AIMS: The aim of the work is to map and describe the patterns of use of nicotine and motivation for use among children and adolescents with problems with addictive substances or in the field of non-addictive addictions. Another aim of the work is to find the degree of physical dependence on nicotine in the target group of respondents. METHODS: Data were collected using a questionnaire, which included Fagerström's nicotine addiction test for adolescents to assess the degree of physical nicotine dependence in respondents. The questionnaire was submitted in paper form to the clients of the Ambulance for children and adolescents addictology of the Clinic of addictology. The research sample was selected by deliberate selection through the institution. Descriptive statistics were used to evaluate the results and...

Magister Scientiae (Medical Bioscience) - MSc(MBS) / Maternal smoking is known to cause serious health risks to the unborn child. Recent studies implicate nicotine as the causative factor. Maternal nicotine exposure during pregnancy and lactation interferes with foetal and neonatal lung growth and development,rendering the lung more susceptible to damage and diseases. Therefore, the aim of this study was to investigate: 1) the effect of maternal exposure to nicotine (1mg/kg BW/day) during all phases of lung development: 2) and vitamin C supplementation (0.5mg/kg BW/day) to prevent the adverse effects of maternal nicotine exposure on lung development in the offspring. This is based on studies in our laboratories which suggested that nicotine reduces the blood and tissue vitamin C content of the mother,thereby rendering the neonate more susceptible to oxidation damage. The chief motivation of this study was to establish whether an anti-oxidant, such as vitamin C, can be administered to smoking pregnant and lactating mothers in order to combat the deleterious effects of nicotine on the lung development of their offspring. It was found that although maternal nicotine exposure had no significant effect on the growth parameters of the offspring, it did have an effect on the development of the lung, compromising the ability of the lung to act as an organ of gaseous exchange. There was a decrease in the surface area available for gas exchange. The change occurred after the lung reached maturation and resembled microscopic emphysema. Vitamin C supplementation was unable to fully protect the neonatal lung against the adverse effects of maternal nicotine exposure; it however partially protected the neonatal lung against structural deterioration. Supplementation with vitamin C definitely offers possibilities as a prophylactic to combat the detrimental influence of maternal nicotine-exposure on foetal and postnatal lung development.

Le tabagisme actif par la mère expose le fœtus en développement à des agents qui peuvent traverser la barrière placentaire et interférer avec les fonctions placentaires. Un large éventail de fonctions immunologiques, pourrait être compromises. Dans cette étude, nous avons évalué l'effet de l'extrait de la fumée de cigarette (CSE) sur les macrophages isolés à partir de placentas humains (pMφs), qui sont les principaux partenaires de l'immunité de fœto-maternelle innée. J’ai pu montrer que le CSE inhibe la formation des cellules géantes multinucléées (MGC). Cette propriété du CSE est spécifique aux macrophages car la fusion des macrophages dérivés des monocytes est inhibée lors de la formation de granulomes in vitro. J’ai également étudié l'absorption de particules et la production de cytokines par pMφs exposés au CSE. Le CSE a inhibé l'absorption des particules de zymosan, mais pas celle du zymosan opsonisé, ce qui suggère qu’il interfère avec les récepteurs phagocytaires et non phagocytaires. Le CSE augmente la libération de TNF et d'IL-33, et une diminue celle de l'IL-10, ce qui montre que l'équilibre entre les cytokines est affecté par le CSE. En outre, l’expression des métalloprotéinases telles que les MMP-1, MMP-10 et MMP-12, connues pour être impliquées dans le remodelage des tissus et la fusion des macrophages est dérégulée. Enfin, j’ai montré que la nicotine, l'un des principaux composés de tabac, n'a pas affecté les propriétés fonctionnelles des pMφs. / Active smoking by the mother exposes the developing fetus to agents that can cross the placental barrier and interfere with placental functions. A wide range of immunological functions, including innate and adaptive immune responses, might be impaired. In this study, we assessed the effect of cigarette smoke extract (CSE) on macrophages isolated from human placentas (pMφs), which are major partners of innate feto-maternal immunity. I showed that CSE significantly inhibited the formation of multinucleated giant cells (MGCs). This property of CSE is specific to macrophages because the fusion of monocyte-derived macrophages is inhibited during the in vitro formation of granulomas. I also investigated particle uptake and cytokine production by pMφs exposed to CSE. CSE inhibited the uptake of zymosan, but not that of opsonized zymosan, suggesting that it interferes with phagocytic receptors, not with the phagocytic machinery of pMφs. CSE increased the release of Tumor Necrosis Factor and interleukin-33, and decreased that of interleukin-10, demonstrating that the balance between inflammatory and anti-inflammatory cytokines is affected by CSE. Furthermore, CSE enhanced the expression of metalloproteinase (MMPs) genes such as MMP-1, MMP-10 and MMP-12, known to be involved in tissue remodeling including macrophage fusion. Finally, I showed that nicotine, one of the major compounds of tobacco, did not affect the functional properties of pMφs.

Les neurones dopaminergiques (DA) de l'aire tegmentale ventrale (VTA) sont au cœur du système de la récompense. Ils sont impliqués dans la transmission de messages liés au contrôle motivationnel et à l'apprentissage par renforcement, permettant de mettre en place des comportements adaptés à l'environnement, mais ont aussi un rôle important dans la mise en place des addictions. Les neurones DA de la VTA projettent majoritairement vers le Noyau Accumbens (NAc) et vers le Cortex Préfrontal (PFC). Ces neurones sont la cible des drogues d'abus qui ont toutes en commun une capacité à augmenter les niveaux de dopamine dans les structures cibles. En effet, les drogues agissent au niveau des neurones DA, ce qui provoque un détournement du système de récompense et mène à l'addiction. La nicotine module le système DAergique à travers ses actions sur les récepteurs nicotiniques à l'acétylcholine (nAChRs), qui sont fortement exprimés dans la VTA. Ainsi la nicotine provoque l'augmentation de la concentration de DA dans les zones de projection, ce qui sous-tendrait le développement de comportements maladaptés liés à une prise de drogue excessive. Néanmoins cette augmentation apparente du relargage de DA dissimule la complexité de la réponse du système DAergique à la nicotine. En effet, les neurones DA forment une population hétérogène qui ne répond pas uniformément ni aux évènements ni aux drogues. Ainsi mon travail s'est focalisé sur la caractérisation de la réponse hétérogène des neurones DA de la VTA à la nicotine. Contrairement à ce qui est communément accepté dans la littérature, la nicotine n'induit pas une augmentation généralisée de l'activité des neurones DA. Ainsi, j'ai pu analyser une sous-population DAergique qui est inhibée par la nicotine. Ces réponses à la nicotine simultanées et opposées sont anatomiquement dépendante, la population inhibée étant localisée de manière plus médiale dans la VTA que la population activée. Nous montrons que cette inhibition requiert l'activation de récepteurs DA inhibiteurs, et pourrait donc être médiée par un relargage de DA intra-VTA. Malgré le fait que nous observons aussi une ségrégation anatomique des réponses DAergiques à des évènements aversifs, ces réponses ne sont pas corrélées à celles induites par la nicotine et sont organisées de manière dorso-ventrale plutôt que médio-latérale, ce qui suggère que le message DAergique transmis en réponse à la nicotine n'est pas le même que celui transmis par l'aversion. De plus, nous avons trouvé que les réponses excitatrices et inhibitrices sont aussi induites pas d'autres drogues d'abus comme l'alcool et les benzodiazépines. Cela suggère que ces réponses peuvent être étendues à d'autres stimuli, mais aussi qu'il existe un principe d'organisation de la VTA qui est anatomiquement défini, par lequel la VTA latérale interagit avec la VTA médiale à travers un effet de réseau local. / Midbrain dopamine (DA) neurons of the ventral tegmental area (VTA) are at the center of the brain's reward system. They are involved in many different brain processes such as motivation, associative learning and reinforcement, and are critically involved in the pathophysiology of addiction. VTA DA neurons mostly project to the Nucleus Accumbens (NAc) and the Prefrontal Cortex (PFC) where they send signals related to motivational control. The common feature of drugs of abuse relates to their ability to increase DA levels in these regions. Indeed, drugs target VTA DA neurons, derailing the system from its natural reward-processing functions, which is thought to be the underlying neurophysiological mechanism leading to addiction. Nicotine is known to modulate the DAergic system through its actions on nicotinic acetylcholine receptors (nAChRs), which are highly expressed in the VTA. This results in an increase of DA concentrations in the areas of projection, which leads to the maladaptive behavior of nicotine addiction. However this apparent increase of DA release conceals the complexity of the system's response to nicotine. Indeed, DA neurons consist of a very heterogenous population, and don't respond uniformly to events or to addictive drugs. Thus my work has focused on the characterization of VTA DA neuron's heterogenous responses to nicotine. In contrast to the commonly acknowledged excitatory effect of nicotine on DA neurons, I've analyzed a subpopulation of DA neurons which are inhibited by nicotine. These concurrent but opposite responses to nicotine occur in an anatomically-dependent manner, with the inhibited population being localized more medially within the VTA compared to the activated population. We show that this inhibition requires the activation of inhibitory dopamine receptors, and could thus be mediated by an intra-VTA DA release. Although we also observe anatomically segregated excitatory and inhibitory responses to painful stimuli, these responses do not correlate to the ones induced by nicotine and are organized in a dorso-ventral fashion rather than a medio-lateral one, suggesting that the DAergic message conveyed by nicotine does not match the one conveyed by aversion. Moreover, we found that concurrent excitatory and inhibitory responses are also induced by other drugs of abuse such as ethanol and benzodiazepines. This suggests that these responses can be extended to other stimuli, but also that there exists an anatomically defined organizing principle of the VTA, in which the lateral VTA interacts with the medial VTA via a local network effect.

Masters of Science / It is well documented that cigarette smoking and nicotine exposure create widespread physiological disorders in humans and animals. The primary tobacco constituent that is responsible for the toxicological consequences associated with the effects of tobacco smoke is nicotine (Van Lancker 1977). After maternal nicotine exposure, the fetal gonads and lungs are the principle sites of nicotine damage (Szuts et al. 1978, Mosier & Jansons 1972). Whilst the fetal lung has received widespread attention in this regard (Maritz 1988), the testis has never been studied. Therefore, I have chosen to explore the effects of maternal nicotine exposure on the testis of male offspring by evaluating various aspects of the male reproductive tract. It is believed that, in adult male smokers (Rosenberg 1987, Handelsman et al. 1984) and sexually mature animals (Mattison 1982) that are exposed to nicotine, male fertility may be compromised. However, these studies provide conflicting data on single parameters. It was therefore my objective to identify the effect of nicotine exposure on the male reproductive tract and to establish possible sites through which these effects may be mediated in adult male rats. The influence of nicotine was then investigated in male offspring after maternal nicotine treatment (MNT), and in sexually mature adult males after direct adult nicotine treatment (ANT). In the former experiment (MNT), 7 day pregnant rats were exposed to Img nicotine/kg body weight/day. Therefore, these offspring were indirectly exposed to nicotine during fetal development and early neonatal development. After weaning the animals were divided into two groups. One group did not receive further treatment (withdrawn group), whilst the other group was continually treated till adulthood (nicotine group), after which both groups were sampled together with the control. In the latter experiment (ANT), the animals were treated daily for 3 weeks and were sampled as above (MNT animals). The fundamental parameter investigated in both experiments to assess reproductive status was sperm quality (motility and morphology). Thereafter, it was necessary to establish a possible site where the effects of nicotine would occur. Testicular growth, epididymal structure, and plasma testosterone content were measured as probable localities of nicotine's effect. The results signify that maternal nicotine exposure poses a greater threat to the male reproductive system than adult nicotine exposure. In the MNT experiment, progressive sperm motility of the nicotine and withdrawn groups were 1.7% and 3.4% respectively. The proportion of abnormal sperm was 72% in each of the above groups. The lower quality sperm that is evident after nicotine exposure implies that the fertilizing ability of the animals may be impaired during adulthood. The data on testicular growth indicates that nicotine exposure during early development results in slower testicular development until maturity. The epididymal lining of these animals also increased after nicotine exposure, indicating increased cellular activity. However, these results from testicular and epididymal studies are inconclusive and need further work. In the ANT experiment, progressive sperm motility of the nicotine group was 1.2%, whilst the proportion of abnormal sperm was 58%. No other parameter was affected after nicotine exposure to adult animals. From the above data it is evident that nicotine exposed animals were subject to greater nicotine damage after maternal nicotine exposure during early development. Moreover, within the maternal nicotine treated experiment, the withdrawal of nicotine after weaning did not appear to reverse the injurious effects of nicotine that were established during early development. These effects were evident since the nicotine and withdrawn groups showed similar levels of damage in all instances. The most profound effects after adult nicotine exposure and maternal nicotine exposure were on sperm quality. The probable site of sperm impairment appears to be via retarded testicular growth and possibly, structural status of the epididymis after maternal nicotine exposure. The results from adult nicotine exposure however, suggest that sperm cells may be directly affected by nicotine exposure. An epidemiological survey was included to validate the basic conclusions established in animal research when compared to clinical data from human patients. No statistically significant changes were observed in this study between the patient's spermiogram results versus his smoking habits, and, that of his mother. From the level of significance it was concluded that cigarette smoking does not appear to be a cause of impaired fertility in already infertile patients. However, the data does suggest that cigarette smoking may well be a precipitating agent in male infertility. Experimentally, nicotine exposure impairs the male reproductive system to some extent. The effects of which are irreversible after indirect exposure (MNT) during development and may begin with poor testicular development. The effects of adult nicotine exposure implies that nicotine exposure in mature animals (ANT) acts directly on sperm cells to incapacitate them. It is well advised that cigarette smoking should be curbed in pregnant women and in adult males to alleviate contributing effects to male infertility.