Tobacco addiction is a leading preventable cause of death worldwide and places a heavy social and financial burden on society. There exists a substantial genetic variability in smoking behavior, the mechanisms of which are largely unknown. Despite significant advances in sequencing power, progress in the identification of genetic variants affecting smoking behavior based on human genome wide association studies has been slow. Thus this thesis investigates the utility of zebrafish as a model species in which to search for genetic variants affecting nicotine seeking. The work is based on the premise that as zebrafish are vertebrate with conserved neurochemical pathways and circuitry with humans, and the pathways involved in drug mediated reward and addiction are evolutionarily ancient, homologues of genes affecting zebrafish nicotine-seeking behavior will likely affect human smoking behavior. Thus results in zebrafish can be used to direct human genetic studies. The first result chapter addresses the hypothesis that zebrafish show conserved reward responses to common drugs of abuse. A conditioned place preference assay is used to assess zebrafish reward responses to stimulants, opioids, benzodiazepines and alcohol. The results indicate that, with the exception of benzodiazepines, reward responses are conserved, supporting the use of this model in a screen for genetic variants affecting nicotine preference. The second and third results chapters describe the findings of a pilot screen of ENU-mutagenized zebrafish provided by the Sanger Institute, Cambridge. I demonstrate that nicotine preference is heritable in fish as in Abstract 5 humans and identify 3 mutant lines that show increased or decreased nicotine place preference. Genotyping indicated that one of the families showing increased nicotine preference carries a predicted loss of function mutation in the slit3 gene. The involvement of this gene in nicotine preference was confirmed in a separate line. Further characterization of this line using qPCR showed slit3 mutants to have altered developmental expression of key nicotinic and dopaminergic genes. Having identified the slit3 gene as a locus affecting nicotine seeking in fish, I then tested the hypothesis that results in fish could be used to predict loci that affect human smoking behavior. Cohorts of patients were genotyped for 20 SNPs within the slit3 locus. Results of this analysis identified 1 novel SNP in the slit3 gene associated with smoking behavior in a cohort of individuals that were heavy smokers. This result was validated in cohorts of low and normal smoking prevalence. These data demonstrate the utility of behavioral assays in zebrafish to identify genes affecting human behavior and pave the way for the use of zebrafish to inform human studies exploring the genetic basis of drug seeking and behavioral disease.

Relapse to drug taking is a major factor contributing to the low success rate of opioid addiction treatment programmes. Recently, studies have revealed a buprenorphine/naltrexone combination had successfully increased the treatment retention rate (compared to naltrexone alone) among heroin addicts (with history of cocaine abuse) who had undergone detoxification. However, buprenorphine and naltrexone could not be administered as a single formulation due to their different bioavailability, which could create compliance issues. Therefore, in this project, we aimed to synthesise a series of ligands each having the pharmacological profile of the buprenorphine/naltrexone combination (partial agonist (ORL-1 receptors), antagonist (u- and x-opioid receptors)). Based on the group's previous work, this profile can be achieved within the orvinols series. Compound BU127, a buprenorphine analogue with phenyl substituent (C20) is very close to the desired profile. Therefore, in order to optimize BU127's profile, we designed and synthesised a series of aromatic analogues, including analogues with a small group attached to the aromatic system to increase the ORL-1 receptor efficacy, while retaining the low efficacy / antagonist activity at the u-opioid receptor and antagonist activity at x-opioid receptor. However, [35S]GTPyS screening has shown a sudden increase of x-opioid receptor efficacy with these modifications. The related compound BU10119, having a Cv-methyl, met the desired profile at all targeted receptors in the [35S]GTPyS screen. A few analogues were selected for further evaluation in functional assays in the isolated tissue preparations (rat vas deferens (for the ORL-1 and u-opioid receptors) and mouse vas deferens (for the K-opioid receptor)) to estimate their binding affinity (Ks) and potency (pA2) of the compounds relative to buprenorphine, using Schild analysis and Schild equation. Of the analogues synthesised, only compounds BU127 and BU1 0119 have met the desired profile at the targeted receptors (competitive reversible at the ORL-1 and u-opioid receptors) and having binding affinity at each receptor similar to buprenorphine (ORL-1, ~- and K-opioid receptors). Based on these results, at this point, the optimum features of buprenorphine analogues in order to achieve the targeted profiles are having a small group at Cy and a 6-membered aromatic substituent at C . 20 Without any substituent group attached to the aromatic ring.

Increasing evidence that ordinary cues paired with reward can acquire value indicates that the incentive properties of rewards are capable of being transferred onto cues, making them incentive stimuli. Studies have begun focusing on isolating components of the reward circuit involved in imparting incentive salience onto a cue with the goal of identifying rats with susceptibilities to drug addiction. Such studies have found that under a Pavlovian Conditioned Approach (PCA) paradigm, sign-tracking rats are at increased risk for instilling incentive salience onto conditioned stimuli and for engaging in drug-related behavior. With better understanding of the neural basis of sign tracking and its behavioral aspect of drug seeking comes a better chance of discovering treatment methods for drug addiction. This study examines the potential behavioral outcomes of altering the pathway starting in the Ventral Pallidum (VP) and ending in the Ventral Tegmental Area (VTA) by using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). While there is some evidence of an interaction between the effects of DREADDs on this neural circuit and behavior, not all results presented here reach significance. Additional studies are needed to confirm the hypothesis of specific inhibitory DREADDs from the VP to the VTA causing increased amounts of sign tracking in rats as a way to assess whether this pathway is implicated in predisposing rats to sign-tracking behavior. / 2018-07-11T00:00:00Z

Inactivity and its negative implications on health, well-being and quality of life are a global issue with around 40% of adults in the UK not meeting physical activity guidelines currently set out by the government. Modern sedentary lifestyle behaviours, such as excessive Internet and video game participation, are contributing factors to this issue. With the rise of households having accessibility to high speed connectivity and devices with the ability to access the Internet and play video games these behaviours are likely to increase. Motivation, Addiction and Sensation Seeking were measured in gamers and surfers using a self-report questionnaire survey. It was thought that both gamers and surfers would share facets of these psychological aspects although participation in their chosen activities usually require different energy expenditures and take place in contrasting environments. Gamers and surfers do share similarities in eight out of the ten aspects of Motivation, Addiction and Sensation Seeking that were measured and showed significantly higher results in measures of Sensation Seeking and Intrinsic Motivation when compared to wider population norms. These findings suggest that both gamers and surfers, in this study, have similar psychological make ups and both groups could be described as intrinsically motivated sensation seekers who have similar levels of risk of addiction to their chosen activities. Therefore the activity of surfing could potentially be used as an intervention or therapeutic lifestyle change that would fulfil important psychological requirements. This would assist in enhancing the health, through exercise, the well-being, through participation in the outdoors environment and therefore the overall quality of life of individuals participating in a sedentary lifestyle behaviour, such as excessive Internet or video gaming.

abstract: Serotonin 1B receptors (5-HT1BRs) are a novel target for developing pharmacological therapies to reduce psychostimulant craving. 5-HT1BRs are expressed in the mesolimbic pathway projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), which is involved in reward and motivation. 5-HT1BR agonists modulate both cocaine- and methamphetamine-seeking behaviors in rat models of psychostimulant craving. In this dissertation, I tested the central hypothesis that 5-HT1BRs regulate cocaine and methamphetamine stimulant and rewarding effects in mice. I injected mice daily with cocaine for 20 days and then tested them 20 days after their last injection. The results showed that the 5-HT1BR agonist CP94253 attenuated sensitization of cocaine-induced locomotion and cocaine-seeking behavior, measured as a decrease in the ability of a cocaine priming injection to reinstate extinguished cocaine-conditioned place preference (CPP). Subsequent experiments showed that CP94253 given prior to conditioning sessions had no effect on acquisition of methamphetamine-CPP, a measure of drug reward; however, CP94253 given prior to testing attenuated expression of methamphetamine-CPP, a measure of drug seeking. To examine brain regions and cell types involved in CP94253 attenuation of methamphetamine-seeking, I examined changes in the immediate early gene product, Fos, which is a marker of brain activity involving gene transcription changes. Mice expressing methamphetamine-CPP showed elevated Fos expression in the VTA and basolateral amygdala (BlA), and reduced Fos in the central nucleus of the amygdala (CeA). In mice showing CP94253-induced attenuation of methamphetamine-CPP expression, Fos was increased in the VTA, NAc shell and core, and the dorsal medial caudate-putamen. CP94253 also reversed the methamphetamine-conditioned decrease in Fos expression in the CeA and the increase in the BlA. In drug-naïve, non-conditioned control mice, CP94253 only increased Fos in the CeA, suggesting that the increases observed in methamphetamine-conditioned mice were due to conditioning rather than an unconditioned effect of CP94253 on Fos expression. In conclusion, 5-HT1BR stimulation attenuates both cocaine and methamphetamine seeking in mice, and that the latter effect may involve normalizing activity in the amygdala and increasing activity in the mesolimbic pathway. These findings further support the potential efficacy of 5-HT1BR agonists as pharmacological interventions for psychostimulant craving in humans. / Dissertation/Thesis / Doctoral Dissertation Neuroscience 2018

Magister Artium (Psychology) - MA(Psych) / Substance use among pregnant women is a perennial problem in the Western Cape Province of South Africa. There are many influential factors are associated with substance use among women of childbearing-age. The study explored factors associated with substance use among pregnant women using a qualitative research design and the bio-ecological theoretical framework to explore and guide the researcher throughout the study. Participants were selected using purposive sampling. Only participants accessed from the Department of Social Development meeting the inclusion criteria of the study were interviewed using semi-structured interviews. Immediate referral for psychological intervention during the interview was available for participants who needed it. Braun and Clarke’s (2006) six phases of thematic analysis were utilised to analyse the data. The study adheres to ethical guidelines for the participants’ protection. Participants were informed about the study before the initiation of the interviews and the details of their voluntary participation were explained. The key findings from this study illustrate that socio-cultural factors, personal factors, emotional response and intimate relationships are the major contributing factors to substance use among pregnant women in this sample. The results outline the preventative measures that pregnant women implement. Lastly, the study reveals the positive and negative perceptions of substance use programmes that participants share. Some of the study findings are similar to the existing literature and some of the findings differed. Recommendations emanating from the study include that the stakeholders, rehabilitation centres, Department of Health and future researchers should act proactively against substance use during pregnancy.

Aims: (1) Analyze the roles of α7 and α4β2 nicotinic receptors (nAChRs) in nicotine sensitization in adolescent male and female rats neonatally treated with quinpirole as well as their effects on brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR) 1 h and 24 h post drug treatment. (2) Analyze the effects of behavioral sensitization to nicotine on α7 and α4β2 nAChR density in the nucleus accumbens and dorsal striatum. Methods: Animals were neonatally treated with quinpirole (1 mg/kg) or saline from postnatal days (P)1-21. Beginning on P33, animals were ip injected with nicotine (0.5 mg/kg free base) or saline and tested every second day from P33-49. Approximately 30 min before injection, animals were ip injected with either the α7 nicotinic receptor (nAChR) antagonist methllycacontine (MLA; 2 or 4 mg/kg) or the α4β2 nAChR antagonist dihyro-β-erythrodine (DhβE; 1 or 3 mg/kg). Brain tissue was taken either 1 h or 24 h after the last day of testing. In a second experiment, animals were identically treated and brain tissue analyzed for nAChR density using the autoradiographic technique. Results: Neonatal quinpirole enhanced nicotine sensitization and the 3 mg/kg dose DhβE effectively blocked nicotine sensitization on Day 9 but enhanced the hypoactive response to nicotine on Day 1. MLA appears more important in the acute response to nicotine. Neonatal quinpirole sensitized the accumbal BDNF response to nicotine, but resulted in a decrease of accumbal mTOR. The nAChR density data will be presented. Conclusions: The α4β2 receptor played a critical role in the development of adolescent nicotine sensitization, and both nAChRs appear to be important in accumbal BDNF and in the mTOR response, demonstrating their important role in synaptic strength.

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This collection of poetry, both narrative and lyric, investigates the geographic identity of rural, southern West Virginia. The poems often inhabit the voices of characters from this geography in order to trace themes of drug addiction, death, and the nature of being a descendent of working-class culture.

Addiction is a national problem in the United States that impacts public health and social and economic welfare. The purpose of this case study was to identify barriers that impede treatment and hinder the success of client recovery from addiction. The research question focused on social work clinicians' perceptions of barriers to effective treatment with substance abuse clients in Coastal South Mississippi. The theoretical framework for this research was the reasoned action theory. Data was collected from a focus group, personal interviews, and the review of literature. Purposeful sampling was used to select 13 social workers for interviews and for a focus group. The social workers needed to have obtained a bachelor or higher degree and a minimum of one year professional experience working with substance abuse clients. Data analysis was conducted by evaluating transcripts of audio recordings from the focus group. The results were then further developed using common words and phrases among the participants to assist in the development of themes. Three themes emerged from this research study: the counselor attitudes/perceptions to treatment, client identified barriers to successful treatment, and the identification of environmental barriers to treatment. The findings of this study might bring about social change by helping social workers to identify factors that influence substance abuse treatment delivery and adapt successful treatment approaches to serve clients by providing social workers with the knowledge and awareness of practitioners' perceptions on treating substance abuse clients. This should lead to enhanced clinical practices by empowering treatment outcomes for the benefit of substance abuse clients.