Rationale: Individuals with addictive disorders commonly exhibit a shortened temporal window, which interferes with treatment focusing on long-term sobriety. Episodic Future Thinking (EFT) involves generating personalized cues related to anticipated, positive events at various future time points. EFT has been shown to reduce the reinforcing value of addictive substances; however, this has only been shown in non-treatment samples. Purpose: To examine the feasibility, cumulative, and sustained effects of implementing EFT in a treatment seeking addiction sample over a 1-week protocol on decision-making and alcohol motivation. Methods: Twenty-eight treatment seeking individuals were randomly assigned to either undergo an EFT intervention or a control Episodic Recent Thinking (ERT) protocol. Assessments were completed at baseline, end of week 1, and a 1-week follow-up. Measures included a delay discounting task, hypothetical alcohol purchase task, clinical outcome measures, and cognitive mechanism measures. Results: There were significant reductions in alcohol demand indices, delay discounting rates, and an increase in mindful attention awareness after both acute and extended exposure to EFT. Furthermore, the EFT group showed greater reductions compared to the ERT group after extended exposure to their cues. Conclusion: The results suggest that early implementation of EFT in a treatment seeking addiction sample is beneficial to counteract motivating factors for relapse. This study lays the foundation for future clinical trials for EFT as a supplemental therapy for addictions treatment. / Thesis / Master of Science (MSc) / People with substance use disorders have a significantly shortened time perspective compared to healthy controls. This means that these individuals struggle with thinking about future events beyond several days to a week. Shortened time perspective can be a significant barrier to addiction treatments that typically focus on long-term positive benefits of sobriety or low-risk use. This study examined whether mindful thinking about future events impacted decision-making and motivation for alcohol and drugs. The study used an experimental protocol known as Episodic Future Thinking (EFT) that involves participants interacting with personalized cues related to positive future events. Prior research using EFT in addiction samples has found that interacting with future cues significantly increases delay of gratification, reduces cigarette use, and decreases reinforcing value of alcohol. In this study, we recruited 28 participants with an alcohol use disorder (AUD). Participants practiced EFT training over a two-week protocol. We tested decision making, alcohol craving, and other variables following a single EFT protocol, and changes in these measures over repeated practice. We found significant changes in alcohol craving, decision making, and mindfulness awareness. The study provides proof-of-concept for using EFT in an AUD treatment population and lays the foundation for future clinical trials of EFT as a complement to existing addiction treatments.

A significant consequence of alcohol use disorders (AUDs) is hippocampal neurodegeneration. The hippocampus is responsible for learning and memory, and neurodegeneration in this brain region has been shown to result in cognitive deficits. Interestingly, some alcoholics demonstrate improvements in hippocampus-dependent functions, potentially due the phenomenon termed adult neurogenesis. Adult neurogenesis, the process by which neural stem cells (NSCs) proliferate, differentiate into neurons, migrate into the granule cell layer, and survive, occurs in two brain regions; however, this study examines only neurogenesis occurring in the subgranular zone of the hippocampal dentate gyrus. Four-day binge ethanol exposure in an animal model causes a decrease in neurogenesis during intoxication; however, there is a reactive increase in cell proliferation on day seven of abstinence. The purpose of this study was to determine the timing of increased cell proliferation. Furthermore, most alcoholics also smoke tobacco, and nicotine, the addictive component of tobacco, has also been shown to affect hippocampal neurogenesis. As many people initiate alcohol and tobacco use during adolescence, the second experiment herein examined the effect of nicotine coadministration on alcohol-induced reactive hippocampal cell proliferation.

An estimated 13.9% of Americans currently meet criteria for an alcohol use disorder. Ultimately, chronic alcohol use may result in neurological deficits, with up to 85% of alcoholics exhibiting signs of cognitive decline. However, biochemical and behavioral factors contributing to this decline have remained elusive. Our ongoing research program encompasses a multi-tiered screening of a natural product library and validation process to provide novel information about mechanisms underlying these deficits and to identify novel chemical scaffolds to be exploited in the development of pharmacological treatments for alcohol use disorders in a rodent organotypic hippocampal slice culture mode. Experiment 1 sought to establish a 48 h high throughput model for testing novel scaffolds against ethanol (EtOH) toxicity. Experiment 2 tested multiple natural product compounds for their ability to attenuate ethanol-induced cytotoxicity. Results from Experiment 1 revealed EtOH (100 mM) induced significant cytotoxicity at 48 h. Trolox (100 µM), a potent antioxidant, was found to reduce ethanol-induced cytotoxicity in this assay. Experiment 2 revealed two spoxazomicins (1, 1-1) demonstrated potent cytoprotective effects against ethanol toxicity. These findings highlight the potential applications of these novel scaffolds for use in the treatment of alcohol use disorder.

Chronic ethanol exposure results in neuroadaptations that drive the progression of an alcohol use disorder (AUD). One such driving force is alcohol-induced neurodegeneration. Neuroinflammation has been proposed as a mechanism underlying this damage. Although neuroinflammation is a physiological response to damage, overactivation of its pathways can lead to neurodegeneration. A hallmark indicator of neuroinflammation is microglial activation, but microglial activation is a heterogeneous continuum of phenotypes that can promote or inhibit neuroinflammation. Furthermore acute microglial activation is necessary to restore homeostasis, but prolonged activation can exacerbate damage. The diversity of microglia makes both the level and timecourse of activation vital to understanding their role in damage and/or recovery. The current set of experiments examines the effects of ethanol on microglia within the hippocampus and entorhinal cortex in a binge model of alcohol-induced neurodegeneration. In the first set of experiments, the phenotype of microglia activation was assessed using Raivich’s 5-stages of activation that separates pro- and anti-inflammatory forms of microglia. Morphological and functional assessments suggest that ethanol does not elicit classical microglial activation but instead induces partially activated microglia. In the second set of experiments, the earliest signs of microglial activation were determined to understand the initiation of microglial activation. Experiments indicated that activation occurred subsequent to previous evidence of neuronal damage; however, activation was accompanied by a loss of microglia and the discovery of dystrophic microglia. The final set of experiments examined whether alcohol-induced partial activation of microglia would show a differential response with further alcohol exposure. Experiments showed that animals previously exposed to ethanol showed a greater response to a second ethanol insult. Overall, these studies suggest that although alcohol may initially interrupt the normal microglia response, during abstinence from ethanol a partial activation phenotype appears that may contribute to recovery. Once activated, however, data suggest that these microglia are primed and upon subsequent exposure show an increased response. This heterogeneous microglial response with respect to time does not necessarily reflect a neuroinflammatory response that would be neurodegenerative but does imply that chronic ethanol consumption affects the normal neuroimmune system.

Bakgrund: Alkoholkonsumtion bidrar till sjukdom, funktionsnedsättning och tidig död världen över. Behandlingsalternativ för den med problematiska alkoholvanor är främst medicinska- och/eller terapeutiska åtgärder. Återfall i det problematiska bruket är dock relativt vanligt. Det föreligger därför ett behov att fortsätta utveckla den vård som ges till personer inom alkoholvården. Fysisk aktivitet är en omvårdnadsåtgärd som sjuksköterskan kan använda för att främja hälsa och lindra sjukdom. Det finns inledande forskning kring den positiva effekt som fysisk aktivitet har för patienter med skadligt alkoholbruk och alkoholberoende men det saknas forskning kring huruvida åtgärden används i det kliniska arbetet. Syfte: Att beskriva sjuksköterskans uppfattningar och erfarenheter av fysisk aktivitet för patienter med skadligt alkoholbruk och alkoholberoende. Metod: Kvalitativ design där semistrukturerade intervjuer genomfördes med sju sjuksköterskor verksamma på mottagningar inom beroendevårdens öppenvård. Som analysmetod användes kvalitativ innehållsanalys. Resultat: Sjuksköterskorna beskrev fysisk aktivitet som en grundläggande del av hälsa och som en nödvändighet i patientens vardag. Fysisk aktivitet var ett sätt för patienten att bryta vanor förknippade med alkohol. Den fysiska aktiviteten ansågs lindra flera av de tillstånd som skadligt alkoholbruk och alkoholberoende för med sig, ökade patientens självkänsla och var ett sätt för patienten att självständigt påverka sin hälsa. Sjuksköterskorna sökte informera och motivera patienten till rätt nivå av fysisk aktivitet. Det saknas struktur för användandet i den kliniska vardagen och sjuksköterskorna efterfrågade praktiska möjligheter och bättre riktlinjer inom verksamheten för att underlätta främjandet av fysisk aktivitet hos patienterna. Diskussion: Resultatet diskuteras utifrån Orems egenvårdsteori samt relevant forskning. / Background: Alcohol consumption contributes to disease, disability and increased morbidity worldwide. Treatment options for those with problematic alcohol use are primarily medical- and/or therapeutic interventions. Relapse in the problematic behaviour is relatively common. There is therefore a need to continue to develop the care provided to people undergoing alcohol treatment. Physical activity is a nursing intervention that the nurse can use to promote healthy lifestyles and alleviate disease. There is preliminary research on the positive impact that physical activity have for patients with alcohol use disorders but no research is to be found on whether the intervention is used in the clinical practice. Aim: To describe nurses' perceptions and experiences of physical activity for patients with alcohol use disorders. Method: Qualitative design with semi-structured interviews was conducted with seven nurses working at outpatient dependence clinics. Qualitative content analysis was used to analyse the data. Results: The nurses described the physical activity as a fundamental element of health and as a necessity in the patient's everyday life. Physical activity was a way for the patient to break habits associated with alcohol. Physical activity was considered to decrease many of the comorbid conditions related to alcohol use, increased the patient's self-esteem and was a way for the patient to independently affect their health. The nurses searched to inform and motivate the patient to the right level of physical activity. There was a lack of structure in the everyday clinical practice and nurses demanded practical possibilities and better guidelines within the organization to facilitate the promotion of physical activity to patients. Discussions: The results are discussed from Orems self-care theory and relevant research.

Previous researchers have indicated that alcohol use disorder affects relationships between family members. Exposure to parental alcohol use disorder disrupts important relationship skill-building development between the children of the family, and may impact conflict resolution in later life relationships. The sibling relationship provides a learning opportunity on how to manage conflict, yet little is known about the effects of parental alcohol use disorder on the sibling-to-sibling relationship from the perspective of adult siblings. The purpose of this descriptive phenomenological enquiry was to explore the lived experiences of adult siblings who experienced parental alcohol use disorder in their family of origin. In-depth, face-to-face interviews were conducted with a purposeful sample of 8 sibling pairs who grew up in the same isolated, remote, and densely populated community, each of whom experienced parental alcohol use disorder. Initial participants were recruited during open 12 Step meetings with subsequent siblings recruited using a snowballing technique. Sixteen audio taped interviews were manually transcribed and then coded for themes using a typology classification system based on key terms, word repetitions, and metaphors. The alcoholic family system was found to be traumatic and abusive, resulting in maladaptive coping behaviors, especially in the area of conflict. Findings also highlighted the strength of the sibling bond in the face of adversity and the opportunity for resilience under challenging circumstances. This study contributes to social change by informing the design of targeted interventions for siblings, specifically, by suggesting a change from the current focus on the identified client to a more holistic approach to treatment.

Alcoholism is a complex neuropsychiatric disease that is characterized by compulsive alcohol use and intensifying cravings and withdrawals, often culminating in physiologic dependency. Fundamental alterations in brain chemistry underlie the transition from initial ethanol exposure to repetitive excessive use. Key mediators of this adaptation include changes in gene expression and signal transduction. Here we investigated gene expression pathways in prefrontal cortex and nucleus accumbens following acute or chronic ethanol treatment, to identify genes with potentially conserved involvement in the long-term response of the corticolimbic system to repeated ethanol exposure. We investigated Gsk3b, which encodes glycogen synthase kinase 3-beta, as a highly ethanol responsive gene associated with risk for long-term maladaptive responses to ethanol. On the level of the protein, we found that GSK3B and to a lesser extent the GSK3A isoform showed robust increases in inhibitory phosphorylation following acute ethanol. This inhibition may underlie aspects of the behavioral response to acute ethanol, as pre-treatment with a GSK3B inhibitor (tideglusib) augmented ethanol’s locomotor effects. Following long term ethanol exposure, we re-tested GSK3B phosphorylation and found that its ethanol response is blunted, consistent with molecular tolerance as a corollary to increased consumption. As the prefrontal cortex (PFC) plays a vital role in the reward pathway via its glutamatergic projections to the nucleus accumbens, we investigated the role of the Gsk3b gene specifically in PFC and in glutamatergic neurons. Overexpression of Gsk3b in the PFC robustly increased ethanol consumption, while deletion in Camk2a-positive neurons significantly attenuated ethanol consumption. Pharmacologic antagonism of GSK3B also decreased drinking in a model of binge-like consumption. Collectively this data implicates GSK3B as a mediator of excessive ethanol intake via its kinase activity, wherein inhibition of the kinase via phosphorylation exerts a protective effect in the context of acute ethanol, but desensitizes with repeated exposure.

Background. Cross-sectional findings in community surveys of adults suggest that adolescent anxiety disorders are strong predictors of the subsequent onset of alcohol use, abuse and dependence. However, prospective data that follow a sample of adolescents into adulthood are needed to confirm these associations. Method. Baseline and 4-year follow-up data from the EDSP-Study, a prospective community survey of 3021 (2548 at follow-up) adolescents and young adults aged 14 to 24 years at baseline carried out in Munich, were used. DSM-IV anxiety disorders, alcohol use and alcohol use disorders were assessed with the Munich-Composite-International-Diagnostic-Interview (M-CIDI). Multiple logistic regression analysis, controlling for age, gender, other mental disorders, substance use disorders and antisocial behaviour was used to study the associations of baseline anxiety disorders with the subsequent onset and course of alcohol use and alcohol disorders. Results. Baseline social phobia significantly predicts the onsets of regular use and hazardous use and the persistence of dependence. Panic attacks significantly predict the onsets of hazardous use and abuse as well as the persistence of combined abuse/dependence. Panic disorder significantly predicts the persistence of combined abuse/dependence. Other anxiety disorders do not significantly predict any of the outcomes. Conclusions. Panic and social phobia are predictors of subsequent alcohol problems among adolescents and young adults. Further studies are needed to investigate the underlying mechanisms and the potential value of targeted early treatment of primary panic and social phobia to prevent secondary alcohol use disorders.

Alcohol use (AU) and alcohol use disorder (AUD) are leading causes of morbidity, premature death, and economic burden. They are also associated with high levels of disability and many other negative outcomes. Twin and family studies have consistently shown that AU and AUD are complex traits influenced by both genetic and environmental factors. Although much has been learned about the genetic and environmental etiology of AU and AUD, significant gaps remain. These include the need for a more comprehensive understanding of the roles of risk and protective factors, and the nature of developmental trajectories underpinning the progression from AU to AUD. The aims of this dissertation are: (1) to examine the roles of resilience and personality disorders in the etiology of AU and AUD; (2) to investigate the nature of longitudinal changes in genetic and environmental risk factors responsible for individual differences in AU; and (3) to determine the moderating roles of key environmental risk factors on the impact of aggregate molecular, or polygenic, risk for AU during adolescence. Using both biometrical behavioral genetic and molecular genetic methodologies, five key findings were observed: (1) Resilience is strongly associated with a reduction in risk for AUD, and this relationship appears to be the result of overlapping genetic and shared environmental influences; (2) Borderline and antisocial personality disorders are the strongest and most stable personality pathology predictors of the phenotypic and genotypic liability to AU and AUD across time; (3) Genetic influences on the development of AUD from early adulthood to mid-adulthood are dynamic, whereby two sets of genetic risk factors contribute to AUD risk; (4) The specific genetic influences on AU follow an unfolding pattern of growth over time, whereas unique environmental risk factors are consistent with an accumulation of environmental impacts and risks across time; and (5) High peer group deviance and low parental monitoring are associated with increased AU, while early parental monitoring moderates the polygenic risk for AU at age 20. The implications of these results with regard to prevention and intervention efforts are discussed.

Abstract: Prior research indicates a growing number of Children of Alcoholics (CoAs) in Sweden, and increased levels of externalizing behaviours in these individuals. According to international research, externalizing behaviours as criminality are more often displayed in CoAs than children with non-alcoholic parents. CoAs are also more often treated for panic attacks, depression and post-traumatic stress. The assumption is that high risk parents often have high risk children. With the aim to investigate the relationship between parental alcoholism and youth criminality in Sweden a systematic literature review has been conducted. Five databases were used to find relevant publications; Libsearch, Swesub, Eric via Ebsco, ProQuest and Google Scholar. A total of 530 texts were scanned and 17 studies eligible to inclusion were read and analysed according to PRISMA, a preferred reporting system of literature reviews. Inclusion criterions were; Sweden as geographical area, attention on children and young adults aged 13-25 years and a focus on parental drinking and youth criminality. The publications were also to be peer reviewed and published between 1998 and 2018. Results indicate a significant correlation between parental drinking and youth criminality in Sweden. CoAs display externalizing behaviours as aggression, conduct disorders, antisocial behaviour and criminality more often than children without alcoholic parents. It can be concluded that research on the field of CoAs is not the most researched in Sweden but in line with international findings and would benefit from further attention so we in the future can work with preventive measures based on solid knowledge.