This project utilized synthesis and in vitro assays to generate antagonist SARs at various nAChR subtypes. Alkylation of the pyridino nitrogen of the nicotine molecule afforded subtype specific antagonists at a42* nAChR subtypes and nAChR subtypes that mediate nicotine-evoked dopamine release. Using this data, a series of mono-azaaromatic quaternary salts were produced and evaluated in binding and functional assays for a42* and a7* nAChR subtypes and nAChR subtypes that mediate nicotine-evoked dopamine release. Additionally, bis-azaaromatic quaternary salts were synthesized and evaluated in the same assays. Two potent lead compounds were identified. N-n-dodecylnicotinium iodide (NDDNI) was found to be very potent at both a42* nAChR subtypes and nAChR subtypes that mediate nicotine-evoked dopamine release. And the most promising candidate was N-N-bisdodecylpicolinium dibromide (bDDPiB), which was selective for the nAChR subtypes that mediate nicotine-evoked dopamine release (IC50 = 9 nM). Additionally, using the data from the SARs, predictive computer models were generated to assist in future compound assessment without in vitro assays. Three self-organizing map (SOMs) models were generated from three different sets of compounds. The groups consisted of the mono-substituted compounds, the bissubstituted compounds, and both sets combined. The models were able to successfully "bin" the test set of compounds after developing a model from a similar set of training compounds. Additionally, using genetic functional activity (GFA) algorithms an evolutionary approach to generating predictive model equations was applied to the compounds. Three separate equations were generated in order to form a predictive method for evaluating affinities at the a4b2* receptor subtype. In addition to the modeling and SAR work of the quaternary ammonium compounds, novel synthetic methods were also employed to develop enantiomerically pure nicotine analogs. Efficient enantioselective syntheses of (S)- and R-(+)-nornicotine, (S)-and R-(+)-anabasine, and (S)-and R-(+)-anatabine have been developed, affording isomers in high enantiomeric excess.

The purpose of this research was to compare and contrast the components and characteristics of selected widely available smoking cessation programs.To reach this goal, an evaluation form was developed after an extensive review of the literature which addressed the structure, duration, techniques, issues which were discussed, success rates and availability of the programs. This form was tested for content validity by a jury of experts and was used to review each of thirteen selected smoking cessation programs. The reviews were conducted by the author using program materials received from the sponsoring organizations. Any questions which could not be answered with these materials were answered through a telephone interview with a representative of the sponsoring organization.Once the reviews were completed, the information was transferred to table form and to a database so that collective data could be generated. The following conclusions were drawn from the table and the data generated: the existing smoking cessation programs appear to have been developed utilizing suggestions offered in to use similar program techniques, and a great deal of variance exists in terms of success rates and cost. / Department of Physiology and Health Science

These results are interpreted as supporting an 'Arousal Modulation' model of cigarette smoking, i.e. smokers can use cigarette smoking as a device for controlling their level of arousal towards an 'optimum' by virtue of the biphasic stimulantdepressant dose response of nicotine and to some extent, by virtue of the effects of smoking behaviour in the absence of nicotine.

There is a large sex difference in the prevalence of attention deficit disorder; yet, little is known about sex differences in prefrontal attention circuitry. We investigated sex differences in the developmental nicotinic excitation of corticothalamic layer VI neurons, which play an important role in attention. Using whole cell recording in prefrontal brain slices, we examined the inward currents elicited by nicotinic stimulation in rodents. We found a prominent sex difference in the currents during the first postnatal month when males had significantly greater α4β2* nicotinic currents. Immunohistochemical analysis of α4YFP mice revealed no sex difference in the pattern or proportion of YFP-positive neurons in layer VI. Further electrophysiological experiments revealed that progesterone is able to rapidly and significantly suppress nicotinic currents in layer VI neurons. This is the first illustration at a cellular level that prefrontal attention circuitry is differently excited by nicotinic stimulation in males and females during development.

Rationale and objectives: Alcohol and nicotine are the most commonly abused drugs and they are often taken together. To help address some of clinical issues regarding nicotine and alcohol co-dependence, a procedure in which rats self-administer nicotine intravenously and alcohol orally during the same operant session has been developed. Methods: Male Wistar rats were trained to self-administer alcohol (12%, w/v; 0.19 ml/delivery) or implanted with jugular catheters and trained to self-administer nicotine (30 μg/kg IV/infusion) by pressing a lever or were trained to self-administer both drugs, some with alcohol first, and others with nicotine first. Results: Animals readily coadministered alcohol and nicotine concurrently. Access to alcohol reduced nicotine selfadministration significantly. Conclusions: These results show that rats will self-administer relevant amounts of intravenous nicotine and oral alcohol concurrently. They also provide further support for the important relationship between nicotine and alcohol.

There is a large sex difference in the prevalence of attention deficit disorder; yet, little is known about sex differences in prefrontal attention circuitry. We investigated sex differences in the developmental nicotinic excitation of corticothalamic layer VI neurons, which play an important role in attention. Using whole cell recording in prefrontal brain slices, we examined the inward currents elicited by nicotinic stimulation in rodents. We found a prominent sex difference in the currents during the first postnatal month when males had significantly greater α4β2* nicotinic currents. Immunohistochemical analysis of α4YFP mice revealed no sex difference in the pattern or proportion of YFP-positive neurons in layer VI. Further electrophysiological experiments revealed that progesterone is able to rapidly and significantly suppress nicotinic currents in layer VI neurons. This is the first illustration at a cellular level that prefrontal attention circuitry is differently excited by nicotinic stimulation in males and females during development.

Rationale and objectives: Alcohol and nicotine are the most commonly abused drugs and they are often taken together. To help address some of clinical issues regarding nicotine and alcohol co-dependence, a procedure in which rats self-administer nicotine intravenously and alcohol orally during the same operant session has been developed. Methods: Male Wistar rats were trained to self-administer alcohol (12%, w/v; 0.19 ml/delivery) or implanted with jugular catheters and trained to self-administer nicotine (30 μg/kg IV/infusion) by pressing a lever or were trained to self-administer both drugs, some with alcohol first, and others with nicotine first. Results: Animals readily coadministered alcohol and nicotine concurrently. Access to alcohol reduced nicotine selfadministration significantly. Conclusions: These results show that rats will self-administer relevant amounts of intravenous nicotine and oral alcohol concurrently. They also provide further support for the important relationship between nicotine and alcohol.

In Canada, nicotine replacement therapy (NRT) is a best practice for adult smoking cessation, but it is not recommended for use by youth smokers. Previous research has indicated that more than 20 percent of high school-aged smokers in Canada had used NRT, despite the cross-Canada requirement that youths under the age of 18 have a physician’s prescription to purchase NRT. The goal of this study was to examine both student and school-level characteristics associated with use of NRT by youths. Data from 29,296 grade 9 to 12 students who participated in the 2008-2009 National Youth Smoking Survey (YSS) were combined with Canadian census and built environment data in multilevel logistic regression models. The associations between lifetime and current NRT use with student characteristics (i.e., smoking status, social smoking connections) were examined alongside school environment factors such as urban/rural location and pharmacy density within a one kilometre radius of schools. In 2008-2009, 21.1% of youth smokers in Canada had ever used NRT and 5.1% were currently using NRT. Odds of NRT use were highest among daily smokers, boys, youths who had made multiple quit attempts, and youths who self-identified as smokers. Attending a school located within an urban area increased youths’ odds of NRT use, whereas higher density of pharmacies surrounding a school was inversely associated with NRT use. This study is the first to identify significant between school differences in NRT use. It also reveals that many youths are using NRT in the absence of a quit attempt. Further research is needed to identify school characteristics that impact NRT use, and understand how youths are accessing NRT.

Thèse (D. en psychologie)--Université du Québec à Montréal, 2005. / En tête du titre: Université du Québec à Montréal. Comprend des réf. bibliogr. Publié aussi en version électronique.

Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2006. / Härtill 4 uppsatser.