published_or_final_version / abstract / toc / Pharmacology / Doctoral / Doctor of Philosophy

A growing body of evidence has established that smoking and gambling frequently co-occur. Despite high rates of co-occurrence, few studies have attempted to examine the extent to which nicotine can directly affect gambling behaviour. This dissertation further explores the relationship between smoking and gambling through a secondary data analysis and two laboratory-based experiments. First, a secondary data analysis was conducted using epidemiological data collected from a gambling prevalence survey in Newfoundland and Labrador. The results from this analysis revealed several associations between smoking and past 12 month gambling. Significant relationships were found between smoking and problem gambling severity scores, use of alcohol/drugs while gambling, money spent gambling, use of video lottery terminals (VLTs), and reasons for gambling related to positive reinforcement/reward and negative reinforcement/relief. Experiment 1 consists of a laboratory investigation of the acute effects of nicotine on subjective and behavioural responses to VLT gambling among gamblers who smoke. Twenty-eight (15 male) regular gamblers who smoke daily took part in two double-blind laboratory sessions where subjective and behavioural responses to gambling were assessed following administration of nicotine inhalers (NI; 4mg deliverable) or placebo inhalers (PI). It was found that NI significantly decreased tobacco-related cravings but did not affect gambling-related cravings, VLT betting, or subjective responses. In Experiment 2, the acute effects of nicotine on subjective, physiological, and behavioural gambling responses were examined in VLT players who smoke following exposure to gambling-related cues. Thirty (20 male) VLT gamblers (identified as ‘moderate risk’ or ‘problem gamblers’) who smoke daily were assigned to a nicotine lozenge (NL; 4mg deliverable) or placebo lozenge (PL) condition. Subjective and behavioural responses were assessed at baseline, following lozenge administration, following neutral cues, and following gambling cues. It was found that NL significantly reduced tobacco-related cravings but didn’t affect gambling-related cravings, the decision to play a VLT, or other subjective responses. The aggregate findings of Experiments 1 & 2 indicate that acutely administered nicotine reduced tobacco-related cravings without increasing the reinforcing value of gambling. These results suggest that use of nicotine replacement therapies (NRT) may be a safe option for gamblers who are attempting to quit smoking.

This study investigated the role of nicotinic acetylcholine receptors (nAChR) in object recognition and spatial recognition memory using the spontaneous object recognition (SOR) and object-location (OL) tasks, respectively. Experiments 1 to 4, did not yield any consistent facilitative effects of systemic nAChR activation with nicotine using 24- and 48-hr delays. Using a 72-hr delay, experiments 5 and 8 revealed that systemic pre-sample nicotine dose-dependently facilitated SOR and OL performance, respectively. Experiments 6-7 and 9-10 investigated the potential involvement of the perirhinal cortex (PRh) and hippocampus (HPC) in these systemic effects, with activation of nAChR in both of these brain regions producing facilitative effects on SOR and OL performance. These results not only demonstrate that nAChR facilitate performance on SOR and OL memory tasks, but suggest these effects are mediated by nAChR action in both PRh and HPC. This study indicates that, even though PRh and HPC are functionally distinct, they can interact to enhance performance on tasks for which they are not entirely necessary. / This research was supported by NSERC and CFI, operating grants to Dr. Boyer Winters.

Smoking cessation leads to weight gain but the reason for this gain is not clearly established. The objective of this study was to compare the mean change in dietary intake among quitters and non-quitters enrolled in a smoking cessation program. Mean dietary intake was measured using 24-hour recall over the telephone at baseline and 6 weeks after the scheduled 'quit date'. Baseline data were obtained from 177 subjects and 130 (73%) were recontacted with complete data. There were 47 quitters (27%). The mean self-reported weight gain among the quitters and non-quitters was 2.4 kg +/- 3.1 and 0.04 kg +/- 2.5 respectively (p = 0.001). Mean energy intake was the same at baseline between the quitters and non-quitters. There were statistically significant changes in dietary intake between quitters and non-quitters. Given the high within-individual variability (sd 832) this sample size was only sufficient to detect differences in the change in intake of approximately 460 kcals between quitters and non-quitters.

A conditioning theory of tolerance postulates a mechanism of a conditioned compensatory response which both modulates the effect of the drug and produces cravings when the drug is not forthcoming. Using measures of heartrate and peripheral vasodilation the author investigated whether reactions opposite in direction to the effects of nicotine such as bradychardia and peripheral vasodilation could be elicited specifically with smokers who are presented with smoking-related stimuli. Due to confounding variables supportive data were not obtained. Recommendations are to conduct future experiments when there is a low differential temperature between the outside and inside, incorporating a more salient conditioned stimulus so control over the conditioned response could be stronger and including more subjects to aid statistical analysis.

Maternal smoking during pregnancy has often been associated with numerous adverse outcomes for the offspring. However, its long-term effects are not well established. Given the high prevalence of maternal smoking during pregnancy, an understanding of these effects is essential. Therefore, the aim of the present dissertation was to shed light on the long-term neurophysiological effects of prenatal nicotine exposure on three different executive functioning processes by assessing participants in young adulthood, using functional magnetic resonance imaging (fMRI). Participants imaged were members of the Ottawa Prenatal Prospective Study, a longitudinal study that collected a unique body of information on participants from infancy to young adulthood, which allowed for the measurement of an unprecedented number of potentially confounding drug exposure variables. The dissertation consists of three separate original manuscripts. In manuscript 1, participants completed a response inhibition task, in manuscript 2 participants completed a verbal working memory task and in manuscript 3 participants completed a visuospatial working memory task. Taken together, results from all three manuscripts showed that prenatal nicotine exposure leads to altered neural functioning during executive functioning processing that continues into young adulthood. These significant results highlight the need for education about the repercussions of women smoking during pregnancy.

There are several lines of evidence supporting the existence of a pivotal role of the cannabinoid system in mediating the reinforcing effects of nicotine. Characterization of the crosstalk between nicotine addiction and the cannabinoid system may have significant implications for our understanding of the neurobiological mechanisms underlying nicotine dependence. Objectives: The current series of experiments, we investigated the effects of activating CB1 receptors, modulating CB2 receptors as well as elevating levels of the endogenous cannabinoid ligand anandamide on nicotine taking and reinstatement of nicotine seeking behaviour. METHODS: In the first series of experiments, we investigated the effects of pretreatment with the CB receptor agonist WIN 55, 212-2 (0.1-1mg/kg), on nicotine self-administration and on the reinstatement of nicotine seeking behaviour. In the next series of experiments, we used a selective CB1 inverse agonist rimonabant (0.3mg/kg) and CB2 antagonist AM630 (5mg/kg) to delineate wether the effects obsereved with WIN 55, 212-2 are CB1 or CB2 meidated. Moreover, we investigated the effect of selective CB2 receptor activation (AM1241 1-10 mg/kg) and inhibition (AM630 1.25-5 mg/kg) on nicotine self-administration under fixed ratio (FR) and progressive (PR) schedules of reinforcement and on reinstatement of nicotine seeking induced by nicotine associated cues and nicotine priming. Finally, the effects of activation of CB receptors through administration of anandamide reuptake inhibitor VDM11 (1-10 mg/kg) on nicotine self-administration and on reinstatement of nicotine seeking were investigated. RESULTS: WIN 55,212-2 enhanced the break points for nicotine self-administration under a PR schedule of reinforcement, reinstated nicotine seeking behaviour and enhanced cue induced reinstatement of nicotine seeking. Neither activation nor blockade of CB2 receptors affected the responding of the animals for nicotine self-administration under FR or PR schedules of reinforcement or for reinstatement of nicotine seeking induced by nicotine associated cues and priming. Pretreatment with VDM11 dose dependently attenuated the reinstatement of nicotine seeking behaviour induced by nicotine associated cues and priming without affecting stable nicotine self administration. CONCLUSION: CB1 but not CB2 receptors appear to play a pivotal role in modulating the reinforcing effects of nicotine. Inhibition of anandamide reuptake could be a potentially useful tool in modulating relapse to smoking

There are several lines of evidence supporting the existence of a pivotal role of the cannabinoid system in mediating the reinforcing effects of nicotine. Characterization of the crosstalk between nicotine addiction and the cannabinoid system may have significant implications for our understanding of the neurobiological mechanisms underlying nicotine dependence. Objectives: The current series of experiments, we investigated the effects of activating CB1 receptors, modulating CB2 receptors as well as elevating levels of the endogenous cannabinoid ligand anandamide on nicotine taking and reinstatement of nicotine seeking behaviour. METHODS: In the first series of experiments, we investigated the effects of pretreatment with the CB receptor agonist WIN 55, 212-2 (0.1-1mg/kg), on nicotine self-administration and on the reinstatement of nicotine seeking behaviour. In the next series of experiments, we used a selective CB1 inverse agonist rimonabant (0.3mg/kg) and CB2 antagonist AM630 (5mg/kg) to delineate wether the effects obsereved with WIN 55, 212-2 are CB1 or CB2 meidated. Moreover, we investigated the effect of selective CB2 receptor activation (AM1241 1-10 mg/kg) and inhibition (AM630 1.25-5 mg/kg) on nicotine self-administration under fixed ratio (FR) and progressive (PR) schedules of reinforcement and on reinstatement of nicotine seeking induced by nicotine associated cues and nicotine priming. Finally, the effects of activation of CB receptors through administration of anandamide reuptake inhibitor VDM11 (1-10 mg/kg) on nicotine self-administration and on reinstatement of nicotine seeking were investigated. RESULTS: WIN 55,212-2 enhanced the break points for nicotine self-administration under a PR schedule of reinforcement, reinstated nicotine seeking behaviour and enhanced cue induced reinstatement of nicotine seeking. Neither activation nor blockade of CB2 receptors affected the responding of the animals for nicotine self-administration under FR or PR schedules of reinforcement or for reinstatement of nicotine seeking induced by nicotine associated cues and priming. Pretreatment with VDM11 dose dependently attenuated the reinstatement of nicotine seeking behaviour induced by nicotine associated cues and priming without affecting stable nicotine self administration. CONCLUSION: CB1 but not CB2 receptors appear to play a pivotal role in modulating the reinforcing effects of nicotine. Inhibition of anandamide reuptake could be a potentially useful tool in modulating relapse to smoking

Diss. (sammanfattning) Uppsala : Univ., 2004. / Härtill 4 uppsatser.

Thesis (Ph.D.)--University of Tennessee Health Science Center, 2007. / Title from title page screen (viewed on July 28, 2008). Research advisor: Burt M. Sharp M.D. Document formatted into pages (viii, 81 p. : ill.). Vita. Abstract. Includes bibliographical references (p. 61-81).