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.

Thesis (MScMedSc)-- Stellenbosch University, 2013. / ENGLISH ABSTRACT: Much has been documented about the detrimental effects of adverse lifestyle factor exposure on the body. Exposure to factors, such as cigarette smoke, have proved to not only be a burden on global health and economy, but have also led to growing concerns about effects on systemic functions such as reproduction. The aim of the present study was to determine the effects of in utero and in vitro nicotine exposure on spermatozoal function and the antioxidant enzyme activity and lipid peroxidation (LPO) status of the male reproductive system. A better understanding of this process is necessary to combat the respective burdens of smoking and male infertility and for the prospective development of treatment strategies. Two experimental models were employed: Wistar rats were exposed to nicotine in utero while human and rat spermatozoa were exposed to nicotine in vitro. In utero studies were achieved by selecting healthy pregnant rats and treating them with 1 mg/kg-bodyweight/day nicotine or 1 ml/kg-bodyweight/day 0.85% physiologic saline throughout gestation and lactation. Male rat pups were selected and sacrificed at each of the following age groups (n=6): 42 days, 84 days and 168 days old. The pups were only exposed to the treatment/saline via placental uptake or lactation. Biochemical analyses of the tissue comprised of measurement of LPO and antioxidant enzyme activity. Results indicated a significant association of maternal nicotine exposure to decreased levels of primary antioxidant enzymes in rat testes. Of particular note was the observation that the treatment group, of which each of the respective antioxidant enzyme levels were significantly less than the control group, was the oldest (d168) rat group. In vitro studies were achieved by collecting sperm samples from healthy human donors (n=12), healthy rats (n=6) and obese rats (n=6). Samples were washed and exposed to different concentrations of high levels of nicotine (Control, 0.1mM, 1mM, 5mM, 10mM) in vitro. Semen parameters such as motility, viability and acrosome reaction were monitored at different time points (30min, 60min, 120min, 180min). Results revealed increasing in vitro nicotine concentrations were associated with decreased viability and acrosomal status of human spermatozoa and decreased progressive motility and viability of rat spermatozoa. Obesity was also associated with decreases in progressive motility and viability of rat spermatozoa. These results indicate that the acute in vitro exposure of spermatozoa to high levels of nicotine could adversely affect semen quality and may be an additive factor to the impediment of male fertility. In utero results reveal maternal nicotine exposure adversely affects male fertility in later life and seems to elicit more detrimental effects on the reproductive system than that of direct nicotine exposure to spermatozoa. Obesity also inhibits parameters of male fertility and these effects are exacerbated by nicotine exposure. The authors believe these adverse effects on the reproductive system to be related to an increased activation of leukocytes, excess production in reactive oxygen species (ROS) and consequent onset of oxidative stress (OS). Nevertheless this study agrees with other studies that nicotine exposure may be an additive factor to the impediment of male fertility. / AFRIKAANSE OPSOMMING: Daar is reeds baie bekend oor die moontlik newe effekte vir die liggaam wat met ‘n ongesonde lewenstyl gepaard gaan. Menslike blootstelling aan sulke faktore, soos sigaret rook, is wêreldwyd ‘n las vir gesondheid en ekonomie en het gelei tot geweldige kommer onder navorsers oor die moontlike komplikasies vir liggaamlike funksies soos voortplanting. Die doel van die betrokke projek was om die effekte van in utero en in vivo nikotien blootstelling op die antioksiderende ensiem aktiwiteit en lipied peroksidasie status van reproduktiewe weefsel en die funksionele parameters van spermatozoa te bepaal. ‘n Beter begrip van hierdie proses is noodsaaklik om die las van rook en vetsug teen te werk en vir die moontlike ontwikkeling van behandelingsstrategieë. Twee eksperimentele modelle is ontwerp: Wistar rotte is in utero blootgestel aan nikotien terwyl mens- en rot- spermatosoë ook in vitro aan nikotien blootgestel is. Vir die in utero studie is gesonde dragtige rotte gedurende swangerskap en laktasie met 1 mg/kgliggaamsgewig/ dag nikotien of 1 ml/kg-liggaamsgewig/dag 0.85% fisiologiese soutoplossing behandel. Manlike welpies is gekies en geoffer op elk van die volgende ouderdomme (n=6): 42 dae, 84 dae en 168 dae. Die welpies is slegs aan nikotien blootgestel deur plasentale opname en laktasie. Biochemiese analise van die testikulêre weefsel het ‘n beduidende assosiasie getoon tussen maternale nikotien blootstelling en verminderde vlakke van die primêre antioksiderende ensieme. Die 168 dag oue groep het ‘n merkbare vermindering getoon tussen kontrole en nikotien weefsel vir elk van die antioksiderende ensieme. Vir die in vitro studie is sperm monsters verkry vanaf gesonde mans (n=12), gesonde rotte (n=6) en vet rotte (n=6). Monsters is gewas en in vitro blootgestel aan verskeie hoë vlakke van nikotien (kontrole, 0.1mM, 1mM, 5mM, 10mM). Seminale parameters soos motiliteit, lewensvatbaarheid en akrosoom status is by verskei tydpunte gemeet (30min, 60min, 120min, 180min). Dit blyk dat verhoging in in vitro nikotien konsentrasies verband hou met verlaagde lewensvatbaarheid en akrosoom status van menslike spermatosoë en verlaagde progressiewe motilteit en lewensvatbaarheid van rot spermatosoë. Vetsug is ook geassosieer met verlagings in progressiewe beweeglikheid en lewensvatbaarheid van rot spermatosoë. In utero resultate openbaar dat maternale nikotien blootstelling manlike vrugbaarheid nadelig beïnvloed in latere lewe en blyk dat dit meer van ‘n nadelige uitwerking op die voortplantingstelsel het as dié van direkte nikotien blootstelling aan spermatosoë. In vitro blootstelling van spermatosoë aan hoë vlakke van nikotien, het wel ook semen kwaliteit nadelig beïnvloed. Vetsug inhibeer ook manlike vrugbaarheids parameters en hierdie effek word vererger deur nikotien blootstelling. Die outeure glo dat hierdie nadelige uitwerking op die voortplantingstelsel verband hou met 'n verhoogde aktivering van leukosiete, oortollige produksie van reaktiewe suurstof spesies en die gevolglike aanvang van oksidatiewe stres bevorder. Hierdie studie stem wel ooreen met ander studies wat nikotien blootstelling bestempel as ‘n bydraende faktor tot die struikelblok van manlike onvrugbaarheid. / Harry Crossley Foundation (South Africa)

Indiana University-Purdue University Indianapolis (IUPUI) / Smoke-free legislation in the United States has unintentionally resulted in a decline in alcohol consumption. However, more recently electronic-cigarettes (e-cigs), which are associated with alcohol use, are reportedly being used to circumvent smoking bans. The present study surveyed community dwelling individuals in the United States reporting e-cigs may be used where they drink (N=365, mean age=33.63, SD=9.91, 53.2% female, 78.9% Caucasian) to examine how e-cig use and alcohol consumption varies by the presence of smoking prohibition where one consumes alcohol. Results indicated that smoking prohibition was associated with a greater likelihood of being an ecig user than a cigarette user (OR=3.40, p<.001) and a higher likelihood of being an e-cig user than a dual user (OR=3.37, p<.001). Smoking prohibition was not associated with AUDIT scores (B=-0.06, p=.21), total drinks (B=-.07, p=.19), or average drinks (B=-0.02, p=.76). E-cig users reported significantly fewer average drinks when smoking is prohibited as compared to allowed, t(55)=3.26, p=.002. Overall, current results suggest smoking prohibition is associated with a greater likelihood of being an e-cig user; however, smoking prohibitions are not associated with alcohol consumption and related problems in the current participants, who all reported being able to use e-cigs where they consume alcohol. Future research should address potential conceptual, methodological, and sample limitations in order to better discern this relationship, as this line of research could have important implications for e-cig policy and alcohol use treatment