Catharanthine is derived from the Catharanthus roseus plant and is an analog to ibogaine, a drug that reduces opioid and alcohol withdrawal symptoms and decreases drug self-administration in both animals and humans. Catharanthine has promise to be an alternative pharmacological treatment for addiction without the adverse side effects associated with ibogaine. The objective of this study was to evaluate catharanthine’s effects on dopamine (DA) transmission in the mesolimbic DA system as well as determine its effects on both ethanol withdrawal induced anxiety and drug-seeking behaviors in mice. We hypothesized that catharanthine would inhibit evoked DA release in the nucleus accumbens (NAc) while also reducing anxiety and drug seeking behaviors in mice. We found that superfusion of catharanthine (1-100 µM) to mouse brain slices significantly inhibits evoked DA release in the NAc of the striatum in a dose dependent manner, while also slowing DA reuptake through inhibition of the dopamine transporter (DAT), measured using fast-scan cyclic voltammetry (FSCV). We also found that intraperitoneal administration of catharanthine in live mice significantly increases extracellular DA, measured via microdialysis with electrochemical detection. Catharanthine inhibition of evoked DA release was significantly reduced by the non-selective nAChR antagonist mecamylamine, the α4 nAChR antagonist dihydro-β-erythroidine hydrobromide (DhβE) and the α6 nAChR antagonist α-conotoxin MII, suggesting that catharanthine inhibits α4 and α6 nAChRs in the NAc. Iontophoresis and in-vivo data indicates that catharanthine slows DA reuptake and increases extracellular DA in the NAc through partial inhibition of DATs. Catharanthine also blocked increases in anxiety-like behavior during ethanol withdrawal in mice in the elevated plus maze. Lastly, preliminary data suggests that catharanthine increases both water and ethanol drinking in a 24-hour two-bottle choice drinking paradigm, which was contrary to our hypothesis.

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Kunskap om vägtrafikens sammansättning behövs för planering av relevanta åtgärder och utvärdering av framtida lösningar inom trafiksystemet. För att öka kunskapsunderlaget om trafikens tillstånd utvecklar Trafikverket Region Stockholm en mätplan för Stockholmsregionen som syftar till att genom mått och indikatorer bättre kunna förklara trafikläget och dess förändring. Behovet av att samordna transporter blir allt större i takt med att befolkningen ökar, men idag finns varierade möjligheter att kartlägga olika grupper av vägtrafiken. Näringslivstransporter pekas ut som ett av Trafikverkets målområden i mätplanen, inom vilka det finns behov av att öka kunskap och dataunderlag. I ett första steg att nå det målet behöver näringslivstransporter beskrivas genom en definition, vilket är det huvudsakliga syftet med detta examensarbete. Definitionen som formulerats, och som beskriver vad som bör betraktas som näringslivstransporter, baseras på information från litteratur och genom intervjuer där begreppet analyserats ur olika perspektiv. Resultatet visar att gruppen är bred och svår att kartlägga eftersom den innefattar en mängd olika transporttyper som genomförs med allt från personbil till stora lastbilar. Eftersom det finns en risk att näringslivstransporter som helhetsbegrepp kan bli begränsat i sin användning genom en för snäv definition har gruppen definierats med aktsamhet. Definitionen delas in i tre kategorier enligt följande: Näringslivstransport av gods, Näringslivstransport av personer och Näringslivstransport av tjänster. Eftersom kunskapsbristen om näringslivstransporter är stor och definitionen ska vara så anpassningsbar som möjligt görs ingen vidare indelning av de tre kategorierna, men exempel på vad varje kategori kan innehålla ges för att förklara hur definitionen kan tillämpas. Det är dock viktigt att poängtera att de olika kategorierna är i olika stort behov av ett ökat kunskapsunderlag baserat på deras omfattning och hur väl de kan kartläggas i olika mätmetoder. Utifrån definitionen genomfördes en dataanalys i syfte att undersöka hur stor del av näringslivstransporter som kan kartläggas i tillgängliga datakällor. Den data som studerades var MCS- och ANPR-data, samt en filminspelning av trafiken. Resultatet visar att det finns goda möjligheter att kategorisera olika typer av lastbilar som kan antas höra till näringslivstransporter genom framför allt ANPR-data, men en del av näringslivstransporter går endast att identifiera genom visuell information såsom logotyper i det filmade materialet. Förslag på vidare studier är att fortsatt kombinera tillgängliga mät- och kartläggningsmetoder, dels i syfte att härleda data till näringslivstransporter, dels för att undersöka vilken typ av information som idag inte kan erhållas om gruppen. Eftersom tidigare studier på näringslivstransporter som helhetsbegrepp är begränsade finns det även behov av att undersöka gruppen vidare, både i sin helhet och undergrupperna för sig. / Knowledge regarding the composition of road traffic is needed for the planning of relevant measures and evaluation of future infrastructure solutions in the transport system. In order to increase knowledge in this area, the Stockholm region of the Swedish Transport Administration is developing a measurement plan that aims to describe the status of the road traffic system and its development using a number of chosen measures and indicators. The need to coordinate transport is increasing with population growth, but today the opportunities to measure different transport categories varies. Commercial vehicles are identified as one of the target areas in the measurement plan, within which there is a need to increase knowledge and explore data sources for further analysis. A step towards achieving this goal is to define what is implied by the term commercial vehicles. This is the main aim of the thesis. The definition of commercial vehicles is based on information obtained from literature and interviews. This information has resulted is a categorization that includes a range of different types of transport. Measuring commercial vehicles is difficult as the definition includes transport carried out by passenger cars as well as trucks. As there is a risk that commercial vehicles as a group may be restricted by a definition that is too narrow, it must be carefully defined. The suggested definition divides commercial vehicles into three main categories: transport of goods, transport of people and transport of services. The aim of this definition is to make it adaptable to specific needs. Examples of what each category may contain, and how the definition can be applied are given in the report. It is important to point out that the different categories are in need of further study in order to increase the knowledge base. Based on the definition, a data analysis was carried out to investigate how commercial vehicles can be explained and measured using three available data sources. The data used included MCS (Motorway Control System), ANPR (Automatic Number Plate Recognition), and film recording. The results showed that there are good opportunities to categorize different types of trucks used for commercial purposes from the ANPR data in particular. However, some attributes of the group can only be identified through visual information such as logos from the film recordings. Proposals for further studies include the need to combine readily available measurement methods and data. Also, as previous studies on commercial vehicles are limited, there is also a need to investigate the group further, both in its entirety and the three categories separately.

Doctor of Philosophy / In healthy individuals, the autoimmune system is the body's natural defense against foreign materials and organisms. The main tools utilized for this defense mechanism are immune cells. However, in patients suffering from autoimmune diseases, the autoimmune system is overactive resulting in its attack on healthy cells, which leads to reduced or eliminated function of the targeted organs. To suppress these overreactive immune responses, pharmaceutical intervention is needed. An integral part of autoimmune response is the lipid sphingosine-1-phosphate (S1P). Interactions of S1P with its response-inducing receptors prompts the release of immune cells, lymphocytes in particular, from lymph tissue to migrate and participate in the invoked immune response. The pharmaceutical industry has produced five FDA approved drugs that disrupt this S1P-receptor interaction by blocking the receptor to reduce the autoimmune response in patients suffering from autoimmune diseases such as multiple sclerosis and ulcerative colitis. However, these treatments had adverse side effects on the cardiovascular system due to the presence of S1P receptors in the heart. Due to this, there is attraction to target a different node of the S1P signaling pathway to avoid these side effects while still suppressing the immune response. A node that is a viable target for therapeutic target that has recently become the focus of medicinal chemistry campaigns is the transporter protein spinster homolog 2 (Spns2). This protein is responsible for the transport of S1P from intracellular space to extracellular space to interact with its receptors and induce the immune response. Recently, our group has developed several effective inhibitors of Spns2. In this dissertation, several improvements of previously reported inhibitors are revealed. The pinnacle of this work is the development of 4.22v that is optimized to have drug-like properties for testing in mice. Administration of 4.22v to mice resulted in reduced circulating lymphocytes and without showing signs of toxicity following chronic dosing for 14 days. These results suggest that 4.22v is a potential drug candidate and is currently undergoing further biological evaluation.

Yes / Recent clinical trials of the hypoglycaemic sodium-glucose co-transporter-2 (SGLT2) inhibitors, which inhibit renal glucose reabsorption, have reported beneficial cardiovascular outcomes. Whether SGLT2 inhibitors directly affect cardiovascular tissues, however, remains unclear. We have previously reported that the SGLT2 inhibitor canagliflozin activates AMP-activated protein kinase (AMPK) in immortalised cell lines and murine hepatocytes. As AMPK has anti-inflammatory actions in vascular cells, we examined whether SGLT2 inhibitors attenuated inflammatory signalling in cultured human endothelial cells. Incubation with clinically-relevant concentrations of canagliflozin, but not empagliflozin or dapagliflozin activated AMPK and inhibited IL-1β-stimulated adhesion of pro-monocytic U937 cells and secretion of IL-6 and monocyte chemoattractant protein-1 (MCP-1). Inhibition of MCP-1 secretion was attenuated by expression of dominant-negative AMPK and was mimicked by the direct AMPK activator, A769662. Stimulation of cells with either canagliflozin or A769662 had no effect on IL-1β-stimulated cell surface levels of adhesion molecules or nuclear factor-κB signalling. Despite these identical effects of canagliflozin and A769662, IL-1β-stimulated IL-6/MCP-1 mRNA was inhibited by canagliflozin, but not A769662, whereas IL-1β-stimulated c-jun N-terminal kinase phosphorylation was inhibited by A769662, but not canagliflozin. These data indicate that clinically-relevant canagliflozin concentrations directly inhibit endothelial pro-inflammatory chemokine/cytokine secretion by AMPK-dependent and -independent mechanisms without affecting early IL-1β signalling. / Project Grant (PG/13/82/30483 to IPS and TMP) and PhD studentships (FS/16/55/32731 and FS/14/61/31284 to DB and AS) from the British Heart Foundation and an equipment grant (BDA11/0004309 to IPS and TMP) from Diabetes UK. OJK was supported by a Scholarship from the Iraqi Ministry of Higher Education and Scientific Research. TAA was supported by a Libyan Ministry of Education PhD Studentship.