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Obesity is a growing problem that impacts both adults and children. Obesity is linked to the development of unfavorable health outcomes like excess fat accumulation in the liver, a problem known as non-alcoholic fatty liver disease (NAFLD). Brown adipose tissue (BAT), a thermogenic body fat that can be turned on by cold, produces heat by consuming circulating lipids and glucose in a futile cycle. Less active cold-stimulated BAT is linked to obesity and type 2 diabetes in adults but whether this relationship exists in children is unknown. In rodents, increases in BAT activity are associated with reductions in NAFLD, effects that may be mediated through changes in the gut microbiome and reductions in peripheral serotonin. Whether the gut microbiome and serotonin play a role in regulating BAT activity in adults and children is not known. In this thesis, we have utilized magnetic resonance imaging (MRI) proton density fat fraction (PDFF) to assess BAT in the supraclavicular (SCV) region after three hours and one hour of whole-body cold exposure in adults and children, respectively. In 60 adults (aged 18-57 years), we examined whether there is a relationship between cold-stimulated BAT activity and liver fat (assessed via MRI) and whether gut microbiota plays a role in connecting these two tissues. In children, we investigated, BAT activity after whole-body cold exposure in 26 boys (aged 8-10 years). We also explored if BAT activity was different between boys with and without overweight/obesity. Finally, in young boys, we measured the levels of serotonin in platelet-poor plasma and its metabolic end product 5-hydroxyindole acetic acid (5-HIAA) in the urine. We explored if these measures of circulating serotonin were related to cold-stimulated BAT activity and if they were different between boys with and without overweight/obesity. The findings from this research indicate that higher cold-stimulated BAT activity is associated with lower liver fat in adults, but that this relationship is unlikely mediated through changes in the gut microbiota. Additionally, boys with overweight/obesity have lower cold-stimulated BAT activity and lower 5-HIAA in their urine compared to those with normal weight. Moreover, circulatory serotonin is negatively related to total adiposity. However, circulating serotonin is not related to cold-stimulated BAT activity in this cohort. These findings are important as they indicate for the first time that increasing BAT activity in adults and children could potentially be a new avenue for the treatment of NAFLD and obesity. / Thesis / Doctor of Philosophy (PhD) / Obesity is a risk factor for the accumulation of extra liver fat, a problem known as non-alcoholic fatty liver disease (NAFLD). Brown adipose tissue (BAT) is a kind of body fat that rather than storing calories like white fat burns calories when switched on by cold. Studies in adults have shown that people with obesity and type 2 diabetes have less active BAT suggesting switching it on may be helpful to promote weight loss and lower glucose. However, whether this relationship exists in children is not known. In rodents, increased BAT activity has also been linked to reductions in NAFLD, effects that might involve a hormone called serotonin, or changes in the gut microbiome but whether this is important in children and adults is also not understood. In this thesis, we utilized magnetic resonance imaging (MRI) to examine BAT activity after whole-body cold exposure in adults (3 hours) and children (1 hour). In 60 adults (aged 18-57 years), we report that higher cold-stimulated BAT activity is linked to NAFLD, but gut microbiota does not seem to play a role in this relationship. In 26 boys (aged 8-10 years), BAT is less responsive to cold in boys with overweight/obesity compared to boys with normal weight. Additionally, serotonin is lower in boys with overweight/obesity compared to boys with normal weight. These findings suggest that increasing BAT activity in adults and children could potentially be a new avenue for the treatment of NAFLD and obesity.

In rats that had been treated neonatally with 6-hydroxydopamine (6OHDA) to deplete striatal dopamine more than 95%, a single injection of p-chloroamphetamine (pCA) (5 or 10 mg/kg, i.p.) resulted in depletion of striatal and hippocampal serotonin at 1 week to a similar extent as in control rats. These findings suggest that striatal dopamine is not essential to the long-lasting depletion of brain serotonin by pCA in rats.

In rat, the neonatal destruction of nigrostriatal dopamine (DA) neurons by intracerebral administration of 6-hydroxydopamine entails dramatic changes in serotonin (5-hydroxytryptamine, 5-HT) as well as DA function. Most striking is the 5-HT hyperinnervation of the adult neostriatum, associated with increases in density of various 5-HT receptor subtypes and enhanced neuronal responsiveness to the iontophoretic application of 5-HT and its 5- HT(1B/2C) and 5-HT(2A/2C) receptor agonists, m-chlorophenylpiperazine and iododimethoxyphenylaminopropane. The topographical distribution of these changes is consistent with up-regulation and/or increased production and transport of 5-HT(1B) and 5-HT(2A) receptors by the neostriatal projection neurons, as confirmed for the 5-HT(2A) receptor in a recent in situ hybridization study. It is interesting that this study has also shown that increases in both 5-HT(2A) binding and mRNA level were abolished by chronic pretreatment with the DA agonists, apomorphine and SKF 38393, suggesting a regulatory influence of DA in the expression of this 5-HT receptor. D1 receptor binding is known to be slightly reduced in the rostral neostriatum of these rats, a down-regulation apparently imputable to a reduced rate of synthesis of the receptor. In contrast, D2 receptor binding is increased throughout the DA-denervated and 5-HT-hyperinnervated neostriatum, perhaps due to some post-transcriptional modifications. Stereotyped and motor behaviors induced by systemic treatment with D1 and D2 agonists are markedly enhanced in these rats (behavioral supersensitivity), although priming is commonly required to unmask a latent D1 supersensitivity. In the case of oral activity, however, overt behavioral supersensitivity is induced by D1 as well as D2 agonists. Moreover, there is overt supersensitivity of oral activity in response to the 5-HT receptor agonist m- chlorophenylpiperazine, which is presumably imputable to 5-HT(2C) receptors and may be demonstrated even in the absence of supersensitivity to D1 receptor agonist. 5-HT adaptations, therefore, seem to play a role not only in the abnormal spontaneous behavior, but also in the behavioral supersensitivity to 5-HT as well as DA receptor agonists in these rats.

Depression is a mental illness that is characterized by a depressed mood, reduced energy levels, loss of interest in activities, and decreased concentration. It is the biggest cause behind the approximately 800 000 suicides committed every year, and one of the largest contributors to global disability. Between 12-55% of all patients suffering from depression do not experience improvement of symtoms after two or more pharmaceutical treatments. Even when the treatments do work, it often takes several weeks for them to acheive full effect.In recent years, research on the antidepressant effects of the controlled substance psilocybin has resumed after a long hiatus. Psilocybin is a psychedelic substance with hallucinogenic, mind-altering properties. It occurs naturally in several species of mushrooms, and has a long history of usage in spiritual rituals by native populations of South America. After ingestion, psilocybin is converted to its active form, psilocin, by enzymes found in the body. Psilocin has a structure similar to serotonin, and the hallucionogenic effects are mediated by psilocin binding to serotonin receptors. The mechanism behind the potential antidepressant effects is not yet fully known, but believed to involve several pathways.This bachelor´s thesis aimed to, through reviewing literature, examine whether psilocybin can constitute a safe and effective treatment for depression. Six scientific studies on the topic were chosen from the databases PubMed and ScienceDirect to be presented in this thesis. All of the chosen studies used established rating scales to evaluate the degree of depressive symtoms before and after one to two doses of psilocybin.The results from the analysed studies indicate that psilocybin, when combined with psychological support, has the potential to constitute a safe and effective treatment for depression. This presupposes that 20-30 mg is administrated in a safe environment with professionally trained indivuduals present. The effect also appears to be long-lasting after only one to two doses, with twelve months being the longest observed period of effect. The number of participants in the studies were however too low to draw any definitive conclusions regarding either effect, safety nor period of effect. More studies with larger study populations are needed to further examine these aspects, and more comparisons with other treatment options are called for.

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Serotonin (5HT) is a monoamine neurotransmitter that modulates a wide range of brain functions via the actions at 5HT receptors and 5HT transporters. Dysregulation of 5HT transmission underlies many neurological and psychiatric disorders, such as depression and anxiety disorders. To advance the research in serotonergic neurotransmission and dysfunction, we have focused on two distinct approaches- 1) investigation of basic biology of synaptic function and 2) small molecule drug discovery. We have first developed a novel fluorescent tracer of 5HT, providing a molecular tool to study the serotonergic system in the CNS with subcellular and cellular resolution in vitro and in vivo. Next, we have developed novel small molecules to activate the serotonin 2A receptor (5HT2A agonists). By exploring new scaffolds, we expect to expand the pharmacophore space for 5HT2A agonists to allow exploration of 5HT2A as molecular target for treating neuropsychiatric disorders, and guide structure-based discovery of more selective 5HT2A agonists with desirable pharmacological properties as potential drug candidates.

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No description available.