Indiana University-Purdue University Indianapolis (IUPUI) / Drug addiction is a behavioral disorder characterized by impulsive behavior and continued intake of drug in the face of adverse consequences. Millions of people suffer the financial and social consequences of addiction, and yet many of the current therapies for addiction treatment have limited efficacy. Therefore, there is a critical need to characterize the neurobiological substrates of addiction in order to formulate better treatment options. In the first chapter, the striatal dopamine system is interrogated with [11C]raclopride PET to assess differences between chronic cannabis users and healthy controls. The results of this chapter indicate that chronic cannabis use is not associated with a reduction in striatal D2/D3 receptor availability, unlike many other drugs of abuse. Additionally, recent cannabis consumption in chronic users was negatively correlated with D2/D3 receptor availability. Chapter 2 describes a retrospective analysis in which striatal D2/D3 receptor availability is compared between three groups of alcohol-drinking and tobacco-smoking subjects: nontreatment-seeking alcoholic smokers, social-drinking smokers, and social-drinking non-smokers. Results showed that smokers had reduced D2/D3 receptor availability throughout the striatum, independent of drinking status. The results of the first two chapters suggest that some combustion product of marijuana and tobacco smoke may have an effect on striatal dopamine concentration. Furthermore, they serve to highlight the effectiveness of using baseline PET imaging to characterize dopamine dysfunction in addictions. The final chapter explores the use of [18F]fallypride PET in a proof-of-concept study to determine whether changes in cortical dopamine can be detected during a response inhibition task. We were able to detect several cortical regions of significant dopamine changes in response to the task, and the amount of change in three regions was significantly associated with task performance. Overall, the results of Chapter 3 validate the use of [18F]fallypride PET to detect cortical dopamine changes during a impulse control task. In summary, the results reported in the current document demonstrate the effectiveness of PET imaging as a tool for probing resting and activated dopamine systems in addiction. Future studies will expand on these results, and incorporate additional methods to further elucidate the neurobiology of addiction.

Indiana University-Purdue University Indianapolis (IUPUI) / Losing a job or a significant other are examples of incentive shifts that result in negative emotional reactions. The occurrence of negative life events is associated with increased drinking, and alleviation of negative emotions has been cited as a drinking motive for individuals with problematic drinking patterns (Keyes et al., 2011; Adams et al., 2012). Further, there is evidence that certain genotypes drink alcohol in response to stressful negative life events (Blomeyer et al., 2008; Covault et al., 2007). It is possible that shared genetic factors contribute to both alcohol drinking and emotional reactivity, but there is a critical need for this relationship to be understood. The first aim of this proposal will use an incentive downshift paradigm to address whether emotional reactivity is elevated in mice predisposed to drink alcohol. The second aim of this proposal will address if reactivity to an incentive shift can result in rash action using a differential reinforcement of low rates of responding task, and whether this response is also associated with a predisposition for high drinking. The third aim of this proposal will investigate if experimenter administered ethanol reduces contrast effects, and if an incentive shift increases ethanol consumption in a high drinking line. The overall goal of this proposal is to investigate whether reactivity to incentive shift is an important mechanism underlying alcohol drinking in these mice, and the role an incentive shift may play in producing rash action and influencing ethanol consumption.

Alcohol use disorder (AUD) is characterized by excessive habitual drinking and loss of control over alcohol intake despite negative consequences. Both of these aspects foster uncontrolled drinking and high relapse rates in AUD patients. Yet, common interventions mostly focus on the phenomenological level, and prioritize the reduction of craving and withdrawal symptoms. Our review provides a mechanistic understanding of AUD and suggests alternative therapeutic approaches targeting the mechanisms underlying dysfunctional alcohol-related behaviours. Specifically, we explain how repeated drinking fosters the development of rigid drinking habits and is associated with diminished cognitive control. These behavioural and cognitive effects are then functionally related to the neurobiochemical effects of alcohol abuse. We further explain how alterations in fronto-striatal network activity may constitute the neurobiological correlates of these alcohol-related dysfunctions. Finally, we discuss limitations in current pharmacological AUD therapies and suggest non-invasive brain stimulation (like TMS and tDCS interventions) as a potential addition/alternative for modulating the activation of both cortical and subcortical areas to help re-establish the functional balance between controlled and automatic behaviour.

Introduktion: ADHD är en uppmärksamhet -och hyperaktiv störning, där 90 % i Sverige behandlas med det farmakologiska läkemedlet Metylfenidat (MPH). En stor andel med ADHD utvecklar psykiatrisk komorbiditet i form av psykisk ohälsa (frånvaro av mentalt välbefinnande). Patofysiologin hur MPH påverkar hjärnan är okänd och behandlingsformen har diskuterats som bristfällig på grund av förekommande bieffekter. Fysisk aktivitet har föreslagits som ett hälsosammare behandlingsalternativ, då evidens visat att fysisk aktivitet kan förbättra ADHD-symptom och samsjuklighet av psykisk ohälsa. Det finns inga studier som undersökt hur individer med ADHD upplever nuvarande- och önskar behandling. Syftet med denna studie blev därför att undersöka upplevda erfarenheter av ADHD och hur det farmakologiska läkemedlet MPH och fysisk aktivitet upplevs ha påverkat diagnosens symptom och individernas psykiska hälsa samt att ta reda på vilken behandling individerna önskar utifrån deras livserfarenheter. Metoden utgick från ett fenomenologiskt ramverk med hjälp av en deskriptiv kvalitativ tvärsnittsstudie, där data extraherades genom en innehållsanalys med en induktiv ansats. Urvalet selekterades genom snöbollsurval, där inklusionskriteriet var att deltagarna blivit diagnostiserad med ADHD och har erfarenheter av MPH och fysisk aktivitet. Resultatet visade att symptom för ADHD var problematik med koncentration-, hyperaktivitet-, uppmärksamhet- och systematiska svårigheter, där symptom försämrat den psykiska hälsan. Det framgick att både MPH och fysisk aktivitet effektiviserade symptom mot koncentration, hyperaktivitet och uppmärksamhet, varav KBT (kognitiv beteendeterapi) förbättrade systematiska svårigheter. Vidare bidrog MPH med fysiska, mentala och beteendeföränderliga bieffekter som försämrade den psykiska hälsan. Fysisk aktivitet visade däremot förbättra den psykiska hälsan, där inaktivitet framgick som en central nackdel för förvärring av symptom och psykisk hälsa. Deltagarnas önskan var att behandling bör uppföljas och baseras på en överenskommelse som anpassas efter individuella svårigheter och hälsotillstånd. Slutsatsen med studien kom fram till att behandlas med fysisk aktivitet i kombination med KBT skulle vara hälsosammare som första behandling mot samtliga ADHD-symptom och psykisk hälsa. I andra hand var det deltagarnas önskan att applicera MPH vid akut behov, och är därav förslag att forska fram MPH som engångsbehandling som kan användas vid inaktiva tillstånd. Studien kom fram till att inkludering av fler idrottsvetenskapliga tjänster till vård och skola behövs för mer kompetens om vikten av fysisk aktivitet för individer som har ADHD. / Introduction: ADHD is an attention-deficit/hyperactivity disorder, where 90% in Sweden is treated with the pharmacological drug Methylphenidate (MPH). People diagnosed with ADHD develop often psychiatric comorbidity in form of mental illness. The pathophysiology behind how MPH influence the brain is unknown and the treatment have been discussed as deficient due to side effects. Physical activity has been suggested as a healthier treatment option, as evidence shows that physical activity can improve ADHD-symptoms and comorbidity of mental illness. There are no studies that have invastigate how individuals with ADHD experience current- and desired treatment. The aim of this study was therefore to investigate the experiences of having ADHD and how the pharmacological treatment MPH and physical activity has affected the symptoms and mental health, and also find out what treatment the individuals want based on their life experiences. The method was derived from a phenomenological framework using a descriptive qualitative cross-sectional study. Data was analyzed with an inductive approach using an interpretive analysis. Participants was recruited through a snowball selection, where the inclusion criteria stated that participants been diagnosed with ADHD and have experience of MPH and physical activity. The results showed that the frequent occurring symptoms of ADHD were difficulties with concentration-, hyperactivity-, attention- and systematic symptoms, where symptoms had shown a negative effect on the mental health. It appeared that both MPH and physical activity made symptom improvement against concentration-, hyperactivity- and attention difficulties, while CBT (Cognitive Behavioral Therapy) improved systematic difficulties. MPH contributed to side effects that affected physiological-, psychological- and behavioral aspects, which all were perceived to have a negative influence on mental health. In contrast, physical activity improved mental health and showed no evidence of side effects, except when physical activity was absent from daily life. Inactivity appeard to be a central disadvantage for worsening symptoms and mental health. The participants desired that their treatment should be tailored to individual difficulties and health condition in a collaborative way and with follow-up from the health care worker. The study concluded that physical activity in combination with CBT would be a healthier as first treatment option to reduce symptoms of ADHD and improve mental heatlh. Additionally, the participants desired treatment with MPH in form of single doses for urgent need, and it is therefore to suggest development of such treatment option. Furthermore, the study proposes more services for sport science within healthcare and schools for containing applicable knowledge in physical activity for dose with ADHD.