Introduction: Maternal smoking is a risk factor for childhood overweight and obesity. However, the mechanisms underlying this association are largely unknown. Smoking is associated with changes in the composition of the maternal microbiome and there is now considerable evidence to suggest that the infant microbiome may play an important role in the development of obesity. Therefore we hypothesized that fetal and neonatal exposure to nicotine, the major addictive component of cigarettes, would result in dysbiosis, an alteration in the composition of the microbiome, in postnatal life. Methods: Nulliparous female Wistar rats were randomized to receive daily injections of saline (N=20) or nicotine bitartate (1.0 mg/kg/d; N=20) from 2 weeks prior to mating until weaning. We assessed markers of inflammation, gut permeability, and the composition of the gut microbiota in the offspring. Results: At the phyla level, exposure to nicotine resulted in alterations in the proportion of both Firmicutes and Bacteriodetes at 26 weeks of age. There were significant changes in a number of operational taxonomic units (OTUs) at 3, 12 and 26 weeks of age. Of note, a number of OTUs for Firmicute Clostridia Clostridiales Lachnospiraceae and Firmicute Clostridia Clostridiales Ruminococcus were decreased in the nicotine-exposed offspring which may suggest increased energy extraction in these animals. Although there was evidence of altered gene expression in pathways regulating inflammation and development, these did not result in increased inflammation or aberrant gut development Conclusion: Maternal nicotine-exposure resulted in dysbiosis in the gut of the offspring; an effect that persisted into adulthood. Since dysbiosis has been associated with increased weight gain and adiposity, these data suggest that alterations in the gut microbiome as a result of maternal nicotine-exposure may explain, in part, the increased risk of obesity in children born to mothers who smoke. / Thesis / Master of Health Sciences (MSc)

The current literature review is aimed to examine the effect of vaping and electronic nicotine delivery on the body. The general population, especially adolescents, may have a misconception about nicotine delivering products being safe or not harmful. However, studies have shown that electronic nicotine delivery systems or products are still detrimental to an individual’s health. This review looks at the impacts of nicotine on the cardiovascular system, the respiratory system, and the brain. The history of electronic cigarettes as well as marketing towards adolescents are also discussed. The results of this literature review indicate that vaping and electronic nicotine delivery systems or products cause harm to an individual’s health although the level of harm, depending on the situation, may not be as severe as that of traditional combustible cigarettes.

Le tabagisme est la cause de longues maladies, responsables chaque année de 6 millions de décès. Le principal composant du tabac, la nicotine, est l'un des psychotropes les plus addictifs. L’abandon du tabac est difficile et les pharmacothérapies les plus efficaces, telles que la varénicline, ne viennent en aide qu’à une proportion limitée des 70% de fumeurs qui souhaitent stopper. Des études cliniques et précliniques ont démontré que plusieurs mécanismes psychopharmacologiques différents contribuent au maintien de la prise de nicotine. Des données psychologiques, génétiques et neurobiologiques, issues d’études cliniques, indiquent désormais que le poids respectif de ces mécanismes psychopharmacologiques pourrait varier d’un fumeur à l’autre. Cette hétérogénéité pourrait contribuer à l’inégale efficacité de la varénicline, dont les cibles psychopharmacologiques sont encore mal connues, ainsi qu’à la faible validité prédictive des modèles précliniques, qui ne tiennent pas compte de cette possible hétérogénéité individuelle. Dans ce travail de thèse, au moyen de l’auto-administration intraveineuse de nicotine chez le rat, nous avons exploré les variations individuelles dans la sensibilité aux effets renforçants primaires de la nicotine et aux effets de la nicotine sur la sensibilité aux effets renforçants de stimuli environnementaux associés. Nous avons mis en évidence trois sous-populations d'individus dont la recherche de nicotine est contrôlée par une contribution différente de ces deux types d’effets de la nicotine. Les phénotypes de ces sous-populations ont été validés par des marqueurs comportementaux préexistants à la consommation de nicotine (l’approche conditionnée pavlovienne), par des marqueurs du métabolisme de la nicotine et des marqueurs neurobiologiques des neurotransmissions cholinergique et dopaminergique dans des structures cérébrales clés. En parallèle, nous avons exploré les cibles psychopharmacologiques de la varénicline. En utilisant une nouvelle approche qui permet de manipuler, pendant l’autoadministration, les effets de la nicotine sur les effets renforçants d’un stimulus environnemental associé, nous avons montré que la varénicline antagonise à la fois ces effets de la nicotine et ses effets renforçants primaires. Néanmoins, dans le premier cas, la varénicline agit d’autant plus que la sensibilité individuelle aux effets de la nicotine est élevée, alors que l’intensité de son effet ne dépend pas de l’amplitude des effets renforçants primaires de la nicotine. Ce travail de thèse met en évidence et valide des variations individuelles dans les mécanismes qui régissent le comportement de recherche de nicotine dans un modèle préclinique. Il offre pour perspective d'explorer les mécanismes neurobiologiques responsables de ces variations individuelles et l’impact à long terme de ces variations sur le développement de la dépendance à la nicotine, ainsi que de tester si la varénicline est plus efficace chez l’une des sous-populations identifiées. / Tobacco use leads to 6 million deaths every year due to severe long lasting diseases. The main component of tobacco, nicotine, is recognized as one of the most addictive drugs, making smoking cessation difficult, even when 70% of smokers wish to do so. Critically, even the most effective pharmacotherapies for smoking cessation, such as varenicline, have only limited efficacy. Clinical and preclinical studies have demonstrated consistently that nicotine seeking is a complex behavior involving various psychopharmacological mechanisms. Critically, converging psychological, genetic and neurobiological data from clinical studies support that the mechanisms controlling nicotine seeking may vary from individual to individual. This heterogeneity could explain the unequal efficiency of treatments, notably of varenicline, whose psychopharmacological targets are still poorly understood, and the poor predictive validity of preclinical models, which do not consider possible individual variations in the mechanisms of nicotine seeking. In this PhD work, using intravenous nicotine self-administration in the rat, we have explored individual variations in the control of nicotine seeking, by the primary reinforcing effects of nicotine, nicotine’s impact on environmental cues, or both. We have evidenced three sub-populations of individuals whose nicotine seeking is controlled by distinct contributions of nicotine primary reinforcing effects and nicotine-cue interactions. Their phenotypes of nicotine seeking have been supported and validated by pre-existing behavioral markers of Pavlovian conditioned approach, as well as by markers of nicotine metabolism, and neurobiological markers of cholinergic and dopamine transmissions in key brain structures. In parallel, we have explored psychopharmacological targets of varenicline. Using a novel approach that allows manipulating the reinforcing-enhancing effects of nicotine on cues, during nicotine self-administration, we evidenced that varenicline antagonizes both these cue reinforcing-enhancing effects and the primary reinforcing effect of nicotine, but as a function of the individual response amplitude for the former, and not for the latter. This PhD work evidences and validates preclinical individual variations in the mechanisms of nicotine seeking. It opens the perspective of exploring the neurobiological causal mechanisms for these individual variations, their long term impact on the development of nicotine dependence and whether varenicline efficacy benefits more to the subpopulation mostly driven by nicotine-induced enhancement of cue reinforcing effects.

Le tabac est consommé par environ un milliard de personnes. D'après l'Organisation Mondiale de la Santé, le tabagisme est la première cause évitable de mortalité dans le monde, provocant six millions de morts par an. La nicotine est le composant neuro-actif principal dans le tabac, et exerce ses effets neurologiques via une activation directe des récepteurs nicotiniques de l’acétylcholine (nAChR). Ces récepteurs transmembranaires sont composés de sous-unités alpha, ou alpha plus beta, créant une variété de canaux ioniques ligand-dépendants activés par le neurotransmetteur ACh. Les études génétiques chez l’homme ont mis en évidence des variants dans le cluster génomique CHRNA5-CHRNA3-CHRNB4, codant pour les sous-unités α5, α3 et β4, comme facteurs influençant le tabagisme. Cette thèse a étudié le rôle des nAChRs contenant la sous-unité β4 (β4*) dans l’addiction à la nicotine. En collaboration, nous avons montré que les souris déficientes pour la sous-unité β4 (β4 KO), sont moins sensibles aux effets récompensant et aversifs de la nicotine. En générant un lentivirus exprimant la séquence murine d'ADN complémentaire de β4, j’ai pu restaurer son expression dans des régions d’intérêt du cerveau, sur un fond génétique β4KO. Ceci a permis de mettre en évidence le rôle du réseau habénulo-interpedonculaire dans la contribution des β4* nAChRs à la consommation de nicotine. Ceci a également démontré le rôle modulateur de ces récepteurs dans les réponses de la voie mésolimbique à la nicotine, voie centrale dans l'effet renforçant des drogues. / Tobacco is consumed by an estimated 1 billion people world-wide. The World Health Organization names tobacco consumption the primary cause of preventable morbidity and mortality, causing six million deaths per year. Nicotine is the principal neuro-active compound in tobacco, and exerts neurological effects by binding to nicotinic acetylcholine receptors (nAChRs). These transmembrane receptors are composed of alpha or alpha plus beta subunits, forming a diverse variety of ligand-gated ion channels endogenously activated by ACh. Human genetic studies have highlighted variants in the CHRNA5-CHRNA3-CHRNB4 genomic cluster, coding for subunits α5, α3 and β4, as altering smoking behaviours. The present thesis investigated the role of β4-containing (β4*) nAChRs in nicotine addiction. In collaboration, we showed that β4 knockout (KO) mice are less sensitive to nicotine reward and nicotine aversion. Generating a lentivirus for the expression of mouse β4 nAChR subunit complementary DNA, I was able to restore receptor expression to brain regions of interest on a KO background, locating the role of β4* nAChR in nicotine reward and aversion to the habenulo-interpedunular pathway. This also demonstrated the receptor’s modulation of nicotinic responses of the mesolimbic system, central hub of drug reinforcement.

Electronic cigarette (ECIG) users can manipulate several device features including liquid nicotine concentration (mg/ml) and heating coil resistance (Ohms). One class of ECIG models, called “sub-Ohm” devices, use coils with a resistance of < 1 Ohms, lower than those observed in conventional ECIGs (e.g., ≥ 1.5 Ohms). Increasing voltage or decreasing coil resistance increases device power. Given that ECIG coil resistance and liquid nicotine concentration have not been manipulated systematically and simultaneously in clinical laboratory studies, the influence of these factors on ECIG acute effects remain unclear. The primary purpose of this study was to examine the influence of coil resistance and liquid nicotine concentration on nicotine delivery, heart rate (HR), subjective effects, puff topography, and liquid consumption. Thirty-two experienced ECIG users completed four independent laboratory sessions that differed by coil resistance (0.5Ohm or 1.5Ohm ) and liquid nicotine concentration (3 or 8 mg/ml). In each session, participants used a 4.5 V “Kanger SUBOX” loaded with 3.5 ml ECIG liquid in a 10-puff directed and 60-minute ad libitum bout. Nicotine delivery was greatest when using 8 mg+0.5Ohm combination and lowest when using the 3 mg/ml+1.5Ohm combination and HR followed a similar pattern. Abstinence symptom suppression was most pronounced for the 8 mg+0.5Ohm combination and least pronounced for the 3 mg/ml+1.5Ohm combination. Participants provided the highest ratings for pleasantness, satisfaction, and liking of harshness/irritancy and throat hit sensations for the 3 mg+0.5Ohm combination. Overall, use of ECIGs filled with 3 mg/ml nicotine concentration resulted in longer/larger puffs, increased puff frequency, and greater consumption of ECIG liquid. ECIG coil resistance, liquid nicotine concentration, and user puff topography, all of which influence ECIG nicotine delivery, should be considered together when making regulatory decisions aimed at protecting public health.

The vast majority of smokers who manage to quit do so without the assistance of a facilitated cessation program. Since the majority of focused anti-smoking efforts are directed at facilitated programs, there is an apparent gap in service of the population at risk. Also, the sharp decline in smoking prevalence indicates a changing demographic dynamic. It is probable that those persons still smoking comprise a different population type than did smokers of a decade ago. A reexamination of major strategies for self-quitting is strongly indicated.The purpose of this thesis was to apply what was known about addictive behavior to a self-guided quitting process. Major variables guiding this effort were learning theory, theory of self-change, empirically demonstrated methods of cessation, and psychosocial effects on lifestyle change.The knowledge gained during the process was incorporated into a menu approach that emphasized personal responsibility for the quitting process and allows for choices that serve to tailor the program to the individual's needs. The end result was a quitters' guide, desktop published and prepared in a small quantity for pilot purposes. This guide was evaluated by persons with particular expertise in addictive behavior, especially smoking cessation. An ammended product was then presented to smokers and/or former smokers for further feedback. A journal of the process that detailed both difficulties and successes was also included. / Fisher Institute for Wellness

Indiana University-Purdue University Indianapolis (IUPUI) / Nicotine is one of the most widely abused drugs in the world, and most smokers begin smoking during their adolescent years. Adolescence is a unique developmental period during which vulnerability to the effects of drug exposure is especially high. This dissertation uses rodent models to investigate the persistent effects of adolescent nicotine exposure on both neurobiological and behavioral measures of drug sensitivity in adulthood. The aims of this dissertation were to 1) determine whether nicotine would be self-administered into the posterior ventral tegmental area (pVTA), a neuroanatomical component of the mesolimbic dopamine (DA) system, which is known to be involved in reward and reinforcement; 2) investigate whether adolescent nicotine exposure would alter the sensitivity of the mesolimbic DA system as measured by DA release in the nucleus accumbens (NAc) in response to nicotine microinjections into the pVTA; 3) examine the effects of adolescent nicotine exposure on behavioral sensitization to nicotine in adulthood; and 4) investigate whether adulthood alcohol drinking behavior, in both Wistar and alcohol-preferring (P) rats, would be augmented by nicotine exposure during adolescence. Results of this dissertation demonstrated that 1) the pVTA is a neuroanatomical site that supports nicotine self-administration; and that adolescent nicotine exposure results in 2) increased nicotine-stimulated DA release in the NAc during adulthood; 3) augmented behavioral sensitization to nicotine in adult animals; and 4) enhanced acquisition of alcohol drinking behavior in adult Wistar and P rats. Overall, this dissertation provides insight into the diverse and persistent changes, in both neurobiology and behavior, caused by exposure to nicotine during the critical developmental period of adolescence.

published_or_final_version / Pharmacology / Doctoral / Doctor of Philosophy

No description available.

No description available.