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Item Co‐administration of ethanol and nicotine heightens sensitivity to ethanol reward within the nucleus accumbens (NAc) shell and increasing NAc shell BDNF is sufficient to enhance ethanol reward in naïve Wistar rats(Wiley, 2019) Waeiss, Robert A.; Knight, Christopher P.; Engleman, Eric A.; Hauser, Sheketha R.; Rodd, Zachary A.; Psychiatry, School of MedicineAlcohol use disorder most commonly presents as a polydrug disorder where greater than 85% are estimated to smoke. EtOH and nicotine (NIC) co‐abuse or exposure results in unique neuroadaptations that are linked to behaviors that promote drug use. The current experiments aimed to identify neuroadaptations within the mesolimbic pathway produced by concurrent EtOH and NIC exposure. The experiments used four overall groups of male Wistar rats consisting of vehicle, EtOH or NIC alone, and EtOH+NIC. Drug exposure through direct infusion into the posterior ventral tegmental area (pVTA) stimulated release of glutamate and dopamine in the nucleus accumbens (NAc) shell, which was quantified through high‐performance liquid chromatography. Additionally, brain‐derived neurotrophic factor (BDNF) protein levels were measured via enzyme‐linked immunosorbent assay (ELISA). A second experiment investigated the effects of drug pretreatment within the pVTA on the reinforcing properties of EtOH within the NAc shell through intracranial self‐administration (ICSA). The concluding experiment evaluated the effect of NAc shell pretreatment with BDNF on EtOH reward utilizing ICSA within that region. The data indicated that only EtOH+NIC administration into the pVTA simultaneously increased glutamate, dopamine, and BDNF in the NAc shell. Moreover, only pVTA pretreatment with EtOH+NIC enhanced the reinforcing properties of EtOH in the NAc shell. BDNF pretreatment in the NAc shell was also sufficient to enhance the reinforcing properties of EtOH in the NAc shell. The collected data suggest that concurrent EtOH+NIC exposure results in a distinct neurochemical response and neuroadaptations within the mesolimbic pathway that alter EtOH reward.Item Effect of epigallocatechin gallate on nicotinetreated Fusobacterium nucleatum biofilm(Office of the Vice Chancellor for Research, 2016-04-08) Kaur, Mandeep; Dhami, Amarjeet; Gregory, Richard L.Abstract Tea polyphenols such as epigallocatechin gallate (EGCG) have exhibited antimicrobial properties. Fusobacterium nucleatum is an oral bacterium that is associated with periodontal diseases. Biofilm adheres to the enamel surfaces of our teeth as plaque. Biofilm formation in the oral cavity leads to many complications such as caries and periodontal diseases. Those who smoke tend to have increased risk of periodontal diseases and F. nucleatum biofilm formation. The objective of this research was to determine the effects of EGCG (0.25 mg/ml) and varying concentrations of nicotine (0-32 mg/ml) on F. nucleatum biofilm. The study was conducted by treating F. nucleatum biofilm with various concentrations of nicotine (0-32 mg/ml) and EGCG. Biofilm formation was measured using a crystal violet dye staining assay and a spectrophotometer. Biofilm formation of F. nucleatum with EGCG and nicotine exhibited a significant decrease in biofilm formation at low concentrations of nicotine (0-4 mg/ml). EGCG alone without nicotine significantly reduces F. nucleatum biofilm formation. EGCG can be added to dental treatments such as toothpaste and mouthwash for those who smoke. Periodontal diseases lead to many health problems in other parts of the body, therefore it is important to find ways to decrease biofilm formation of F. nucleatum.Item Effect of nicotine on cariogenic virulence of Streptococcus mutans(Springer, 2016-11) Li, Mingyun; Huang, Ruijie; Zhou, Xuedong; Qiu, Wei; Xu, Xin; Gregory, Richard L.; Department of Biomedical and Applied Sciences, IU School of DentistryNicotine has well-documented effects on the growth and colonization of Streptococcus mutans. This study attempts to investigate the effects of nicotine on pathogenic factors of S. mutans, such as the effect on biofilm formation and viability, expression of pathogenic genes, and metabolites of S. mutans. The results demonstrated that addition of nicotine did not significantly influence the viability of S. mutans cells. The biofilms became increasingly compact as the concentrations of nicotine increased. The expression of virulence genes, such as ldh and phosphotransferase system (PTS)-associated genes, was upregulated, and nlmC was upregulated significantly, while ftf was downregulated. The lactate concentration of S. mutans grown in 1 mg/mL of nicotine was increased up to twofold over either biofilm or planktonic cells grown without nicotine. Changes in the metabolites involved in central carbon metabolism from sucrose indicated that most selected metabolites were detectable and influenced by increased concentrations of nicotine. This study demonstrated that nicotine can influence the pathogenicity of S. mutans and may lead to increased dental caries through the production of more lactate and the upregulation of virulence genes.Item Effect of Nicotine on Planktonic and Biofilm Growth Phases of an Experiment(Office of the Vice Chancellor for Research, 2014-04-11) Gupta, Vinayak; Gregory, Richard L.Tobacco and cigarette smoke increase the risk of periodontal disease, one of the most widespread human diseases. It has been established that Porphormonas gingivalis, a gram negative anaerobic bacterium, is one of the main causative agents of periodontal disease. Prior research indicates that P. gingivalis binds to Fusobacterium nucleatum in oral biofilms. It is not yet understood if nicotine, a major component of cigarette smoke, affects the growth of bacteria differently if added in the planktonic phase, defined as the primary subculture from agar to broth before the start of a biofilm formation experiment, or the biofilm phase, defined as the secondary subculture from broth culture to a microtiter plate. Therefore, the main objective of this study is to understand this methodological difference. F. nucleatum and P. gingivalis were both grown in anaerobic GasPak containers on blood agar plates. The media for primary subculture consisted of a Brain Heart Infusion (BBL) broth supplemented with 5 g/L yeast extract and 5% vitamin K & hemin serum at 37oC. F. nucleatum was subcultured in the absence of nicotine and plated on a 96 well plate to establish biofilm. P. gingivalis was subcultured in varying concentrations of nicotine and subcultured on top of the F. nucleate biofilm. Biofilm mass was analyzed using the crystal violet technique and samples were measured in a spectrophotometer at 490 nm. The results demonstrated a statistically significant increase in biofilm formation when P. gingivalis was subjected to a higher nicotine concentration in the planktonic phase in comparison to a lower nicotine concentration in the biofilm phase. This data suggests a nicotine assisted activation of receptors on the surface of P. gingivalis specific for binding to F. nucleatum. Further testing on the receptors through a biotinylation assay will confirm the results.Item Effects of Nicotine Exposure in Adolescent Rats on Acquisition of Alcohol Drinking and Response to Nicotine in Adulthood(2009-09-30T19:25:40Z) Bracken, Amy L.; McBride, William J.; Chambers, R. Andrew; Murphy, James M.; Rodd, Zachary A.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.Item The Effects of Nicotine on the Proteolytic Activity of Periodontal Pathogens(2011) Kaeley, Janice,1976-; Gregory, Richard L.; Blanchard, Steven B.; Kowolik, Michael J.; Windsor, L. Jack; Zunt, Susan L., 1951-Periodontal disease is the leading cause of tooth loss in adults. Bacterial biofilm on tooth surfaces is the primary initiator of periodontal disease. Various factors contribute to the severity of periodontal disease including the different virulence factors of the bacteria within the biofilm. In the progression of periodontal disease, the microflora evolves from a predominantly Gram positive microbial population to a mainly Gram negative population. Specific gram negative bacteria with pronounced virulence factors have been implicated in the etiology and pathogenesis of periodontal disease, namely Porphyromonas gingivalis, Tannerella forsythia and Treponema denticola which form the red complex of bacteria. The orange complex bacteria become more dominant in the maturation process of dental plaque and act to bridge the early colonizers of plaque with the later more dominant red complex bacterial and consists of such bacteria as Campylobacter showae, Campylobacter rectus, Fusobacterium nucleatum and Prevotella intermedia. Perhaps the most investigated contributing factor is the relationship between smoking and periodontal disease. When examining the association between cigarette smoking and interproximal bone loss, greater bone loss is associated with higher cigarette consumption, longer duration (i.e., pack year history) and higher lifetime exposure. The presence of various virulence factors such as the production of a capsular material, as well as the proteolytic activity of the various periopathodontic bacteria has been associated with the pathogenesis of periodontitis. Even though many different enzymes are produced in large quantities by these periodontal bacteria, trypsin-like enzymes, chymotrypsin-like enzymes and elastase-like enzymes, as well as dipeptidyl peptidase-like enzymes, have been thought to increase the destructive potential of the bacterium and mediate destruction of the periodontal apparatus. More specifically, it is hypothesized that the proteolytic activity of other clinically important periodontal pathogens, such as Fusobacterium nucleatum, Prevotella intermedia and Porphyromonas assacharolyticus, is increased in the presence of nicotine. The purpose of this study was to determine the effects of nicotine on F. nucleatum, P. intermedia and P. assacharolyticus proteolytic activity. Cultures were maintained on anaerobic blood agar plates containing 3% sheep blood. Bacterial cells were harvested from the plates and washed. Washed F. nucleatum, P. intermedia and P. assacharolyticus cells were incubated with 1 mg/ml of nicotine. Bacterial cells not incubated with nicotine were used as positive controls. Secreted enzymatic activity was measured using the synthetic chromogenic substrates glycyl-L-proline-p-nitroanilide (GPPNA), N-succinyl-L-alanyl-L-alanyl-L-alanyl-p-nitroanilide (SAAAPNA), N-succinyl-alanine-alanine-proline-phenylalanine-p-nitroanilide (SAAPPPNA) and N-α-benzoyl-L-arginine-p-nitroanilide (L-BAPNA) (Sigma-Aldrich Products, St. Louis, MO, USA). Appropriate means and standard deviations were determined for each of the enzymatic activities measured and analysis of variance (ANOVA) was used to compare the groups utilizing a 5% significance level for all comparisons. Results demonstrated that after 60 minutes of incubation of F. nucleatum, P. intermedia and P. assacharolyticus cells with 1 mg/ml of nicotine and the various synthetic substrates, had the following proteolytic activity for GPPNA: 0.83 ± 0.14, 0.72 ± 0.03 and 0.67 ± 0.10, respectively; SAAAPNA: 0.82 ± 0.06, 0.76 ± 0.05 and 0.68 ± 0.08, respectively; SAAPPPNA: 0.90 ± 0.13, 0.85 ± 0.17 and 0.72 ± 0.03, respectively; and BAPNA: 0.81 ± 0.15, 0.74 ± 0.13 and 0.74 ± 0.16, respectively. In conclusion, the results indicate that in the presence of 1 mg/ml of nicotine, the proteolytic activity of F. nucleatum and P. assacharolyticus was increased with all of the synthetic substrates (with statistical significance seen only in the increases with F. nucleatum and GPPNA, SAAAPNA and BAPNA). The proteolytic activity exhibited an increasing trend in activity for P. intermedia with SAAPPPNA and BAPNA but a decreasing trend in activity with GPPNA and SAAAPNA when incubated with 1 mg/ml of nicotine, once again demonstrating no statistical significance for any of the substrates. Therefore, it could be concluded that based on these results nicotine at a concentration of 1 mg/ml may increase the proteolytic activity of periodontal pathogens and thus may increase periodontal disease activity and subsequent periodontal breakdown. Further studies are needed to validate these results utilizing different concentrations of nicotine.Item Exome chip meta-analysis fine maps causal variants and elucidates the genetic architecture of rare coding variants in smoking and alcohol use(Elsevier, 2018) Brazel, David M.; Jiang, Yu; Hughey, Jordan M.; Turcot, Valérie; Zhan, Xiaowei; Gong, Jian; Batini, Chiara; Weissenkampen, J. Dylan; Liu, MengZhen; Barnes, Daniel R.; Bertelsen, Sarah; Chou, Yi-Ling; Erzurumluoglu, A. Mesut; Faul, Jessica D.; Haessler, Jeff; Hammerschlag, Anke R.; Hsu, Chris; Kapoor, Manav; Lai, Dongbing; Le, Nhung; de Leeuw, Christiaan A.; Loukola, Anu; Mangino, Massimo; Melbourne, Carl A.; Pistis, Giorgio; Qaiser, Beenish; Rohde, Rebecca; Shao, Yaming; Stringham, Heather; Wetherill, Leah; Zhao, Wei; Agrawal, Arpana; Bierut, Laura; Chen, Chu; Eaton, Charles B.; Goate, Alison; Haiman, Christopher; Heath, Andrew; Iacono, William G.; Martin, Nicholas G.; Polderman, Tinca J.; Reiner, Alex; Rice, John; Schlessinger, David; Scholte, H. Steven; Smith, Jennifer A.; Tardif, Jean-Claude; Tindle, Hilary A.; van der Leij, Andries R.; Boehnke, Michael; Chang-Claude, Jenny; Cucca, Francesco; David, Sean P.; Foroud, Tatiana; Howson, Joanna M. M.; Kardia, Sharon L. R.; Kooperberg, Charles; Laakso, Markku; Lettre, Guillaume; Madden, Pamela; McGue, Matt; North, Kari; Posthuma, Danielle; Spector, Timothy; Stram, Daniel; Tobin, Martin D.; Weir, David R.; Kaprio, Jaakko; Abecasis, Gonçalo R.; Liu, Dajiang J.; Vrieze, Scott; Medical and Molecular Genetics, School of MedicineBackground Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences, and contribute to disease risk. Methods We analyzed ∼250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss of function coding variants. We performed a novel fine mapping analysis to winnow the number of putative causal variants within associated loci. Results Meta-analytic sample sizes ranged from 152,348-433,216, depending on the phenotype. Rare coding variation explained 1.1-2.2% of phenotypic variance, reflecting 11%-18% of the total SNP heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between 3 and 10 variants for 65 loci. 20 loci contained rare coding variants in the 95% credible intervals. Conclusions Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine mapping GWAS loci identifies specific variants contributing to the biological etiology of substance use behavior.Item Exploration of Endothelial Cell Invasion and Responses to Nicotine and Arginine by Streptococcus Mutans Serotype K Strains in a Sucrose-Induced Biofilm Lifestyle(2019-08) Wagenknecht, Dawn R.; Gregory, Richard L.; Windsor, L. Jack; Galli, Dominique M.; Lee, Chao-Hung; Ji, Julie; Childers, Noel K.Streptococcus mutans, an inhabitant of oral biofilm or dental plaque, adheres to the tooth surface via protein antigen I/II (PA I/II). Pathologic lesions of atherosclerosis (AT) and infective endocarditis (IE) harbor S. mutans. Serotypes f and k strains with collagen binding protein genes cbm and cnm are uncommon in the mouth, but these are the most prevalent S. mutans strains in AT and IE tissues and can invade endothelial cells (EC) in vitro. Tobacco use increases the risk for cardiovascular and oral diseases. Oral S. mutans encounter many substances including nicotine. Arginine is present in saliva and the EC glycocalyx that coats and protects ECs from shear forces of blood flow. Prior studies demonstrated arginine alters S. mutans biofilm. This work characterizes S. mutans serotype k strains and serotype c strains, the most prevalent in the mouth. The effects of nicotine and arginine on biofilm mass, metabolic activity and EC invasion were investigated. Biofilm production by serotypes c and k strains did not differ; there were no differences in responses to nicotine and arginine between these serotypes. Increased production of biofilm was associated with the cbm and cnm genes. Nicotine increased biofilm for all strains whereas arginine plus nicotine reduced bacteria and the extracellular polymeric substances. Previous EC invasion studies were performed with planktonic cultures of S. mutans; therefore, EC invasion by biofilm was evaluated. Significant factors for EC invasion by S. mutans are presence of the cbm gene and lack of PA I/II expression on the bacterial cell surface. Presence of the cnm gene increased EC invasion by biofilm but not planktonic cells. Planktonic cells of six strains invaded better than biofilm, whereas four strains showed increased invasion by biofilm cells. Neither nicotine nor arginine significantly altered the ability of S. mutans biofilm cells to invade ECs. Not all strains with cbm or cnm and no PA I/II expression invaded EC. A strain with PA I/II expression and without cbm and cnm genes invaded EC. While cbm, cnm and PA I/II expression are predictors of EC invasion, additional mechanisms for EC invasion by S. mutans remain to be revealed.Item An improved model of ethanol and nicotine co-use in female P rats: Effects of naltrexone, varenicline, and the selective nicotinic α6β2* antagonist r-bPiDI(Elsevier, 2018-12) Maggio, Sarah E.; Saunders, Meredith A.; Nixon, Kimberly; Prendergast, Mark A.; Zheng, Guangrong; Crooks, Peter A.; Dwoskin, Linda P.; Bell, Richard L.; Bardo, Michael T.; Psychiatry, School of MedicineBackground Although pharmacotherapies are available for alcohol (EtOH) or tobacco use disorders individually, it may be possible to develop a single pharmacotherapy to treat heavy drinking tobacco smokers by capitalizing on the commonalities in their mechanisms of action. Methods Female alcohol-preferring (P) rats were trained for EtOH drinking and nicotine self-administration in two phases: (1) EtOH alone (0 vs. 15% EtOH, 2-bottle choice) and (2) concomitant access, during which EtOH access continued with access to nicotine (0.03 mg/kg/infusion, i.v.) using a 2-lever choice procedure (active vs. inactive lever) in which the fixed ratio (FR) requirement was gradually increased to FR30. When stable co-use was obtained, rats were pretreated with varying doses of naltrexone, varenicline, or r-bPiDI, an α6β2* subtype-selective nicotinic acetylcholine receptor antagonist shown previously to reduce nicotine self-administration. Results While EtOH intake was initially suppressed in phase 2 (co-use), pharmacologically relevant intake for both substances was achieved by raising the “price” of nicotine to FR30. In phase 2, naltrexone decreased EtOH and water consumption but not nicotine intake; in contrast, naltrexone in phase 1 (EtOH only) did not significantly alter EtOH intake. Varenicline and r-bPiDI in phase 2 both decreased nicotine self-administration and inactive lever pressing, but neither altered EtOH or water consumption. Conclusions These results indicate that increasing the “price” of nicotine increases EtOH intake during co-use. Additionally, the efficacy of naltrexone, varenicline, and r-bPiDI was specific to either EtOH or nicotine, with no efficacy for co-use. Nevertheless, future studies on combining these treatments may reveal synergistic efficacy.Item An in-vitro comparison of four antibacterial agents with and without nicotine and their effects on human gingival fibroblasts(Wiley, 2021) Batra, Chandni; Alalshaikh, Marwa; Gregory, Richard L.; Windsor, L. Jack; Blanchard, Steven B.; Hamada, Yusuke; Periodontology, School of DentistryBackground To compare anti-bacterial activity of 0.12% Chlorhexidine (CHX), 10% Povidone Iodine (PVD), Vega Oral Care Gel (VEGA), and Antioxidant Gel (AO) on Streptococcus mutans, Streptococcus sanguis, Fusobacterium nucleatum, and Porphyromonas gingivalis with and without nicotine and to evaluate their effects on human gingival fibroblasts (HGFs). Methods S. mutans, S. sanguis, P. gingivalis, and F. nucleatum were incubated with serial dilutions (1/4, 1/8, 1/16, 1/32, and 1/64) of anti-bacterial agents in media (with and without nicotine). Minimum inhibitory and minimum bactericidal concentrations (MIC/MBC) were measured, and confocal microscopy was performed. HGFs were exposed to serial dilutions (1/10, 1/100, 1/1000, and 1/10,000) of antibacterial agents with media. Water-soluble tetrazolium-1 (WST-1) assay and lactate dehydrogenase (LDH) assay were used to assess proliferation and cytotoxicity towards HGFs. Results CHX and PVD significantly inhibited growth of all bacterial species (P < 0.0001) at all dilutions. AO and VEGA inhibited growth of all bacterial species up to only the 1/4 dilution. CHX and PVD decreased HGF proliferation at 1/10 and 1/100 dilution, whereas AO at all dilutions (P < 0.05). CHX and AO were cytotoxic at all dilutions (P < 0.05). VEGA was not cytotoxic to HGFs and did not affect HGF proliferation at any dilution (P > 0.05). An increased bacterial growth was seen for all species except P. gingivalis with addition of nicotine. Conclusion CHX and PVD demonstrate superior antibacterial properties, but significantly reduce HGF proliferation. AO is bacteriostatic at lower dilutions but is highly toxic to HGFs. VEGA was bacteriostatic and demonstrated no detrimental effects on HGF's.
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