Anti-depressants are commonly used to treat major depression and post-traumatic stress disorder. 17% of women experience major depression during pregnancy, where up to 10% of pregnant women use antidepressants. 20% these women use Prozac (fluoxetine) to treat major depressive symptoms, which crosses the placental barrier and is present in breast milk. Little is known about how exposure to developmental fluoxetine affects adulthood behaviors such as agonistic and submissive behaviors, especially in females. Furthermore, the effects of developmental fluoxetine exposure on aggression and avoidance in Syrian hamsters have not been studied. Therefore, we explored how prenatal and perinatal exposure to fluoxetine affects adulthood aggression and avoidance in male and female Syrian hamsters. Dams were given fluoxetine via drinking water 7 days prior impregnation. Fluoxetine administration continue until offspring reached postnatal day (PD) 12. The offspring were weaned and group-housed at PD 25 and single-housed at PD 60. Animals were handled one week prior to behavioral testing. The following week, animals were tested for aggression in a neutral arena with a non-aggressive stimulus hamster of the same sex. Another group of hamsters were tested for avoidance behavior in a neutral arena 24 hours after social defeat. Duration of aggression and avoidance were quantified. There was no main effect of sex or drug nor was there an interaction. Therefore, we reject our hypothesis of prenatal and perinatal exposure to fluoxetine will affect aggression and avoidance in male and female Syrian hamsters. These findings may be due to a ceiling effect in Syrian hamsters, where the subtle effects of developmental fluoxetine exposure were not observable.

Syrian hamsters are a useful model for offensive aggression because males and females spontaneously engage in agonistic bouts. In hamsters, there is a large sex difference on aggression in the serotonin (5-HT) pathways. Male aggression is inhibited and female aggression increases with injections of a 5-HT agonist into the anterior hypothalamus (AH), but little is known if similar effects are seen in adult hamsters with repeated systemic administration of the selective serotonin reuptake inhibitor (SSRI), fluoxetine (FLX), which is one of the few approved pharmacological treatments for mood disorders in children and adolescents. The goal of this study is to determine if repeated intraperitoneal injections of FLX over 30 days in adolescent male and female hamsters has an effect on offensive aggression similar to site specific alterations of the 5-HT system in the AH. Our data suggest that systemic administration of FLX as adolescents over 30 days does not affect offensive aggression in males or females as adults.

Depression is one of Sweden's most common diseases. In recent years, more and more children and adolescents are diagnosed with depression and the disease continues to increase in numbers. Most common causes of depression are any kind of stress, trauma, surrounding impacts and inherited symptoms. Due to this, prescriptions of antidepressants have increased and the most commonly used drugs for children and adolescents are SSRI-drugs. The purpose of this study is to examine the underlying reasons for increased prescription of antidepressants. I will also investigate how many children there is who currently takes antidepressants in Sweden and how many children there is suffering from depression. The study will be conducted through two different methods, a registry study and through interviews. For the interview study, five respondents were chosen all with different task assignments like counselors, psychologists, and child psychiatrists. The result for this study all showed that the prevalence of depression continues to increase. In 2015 6 % of children in Sweden aged 0-19 were diagnosed with depression. Although the number of prescriptions on SSRI-drugs almost doubled during the last ten year period, this group of drugs constitutes the treatment option for only one fifth of the patients. The treatment of choice is cognitive behavior treatment for mild and moderate depression. Factors that are contributing to a diminished mental health among young people according to the interviews among healthcare professionals are both a changed society but also changed lifestyles that are major causes. Children feel more stress and demands in today's society that has been a contributing factor. They will nowadays make more decisions and plan their time and schooling, something that younger children cannot handle. Factors that might explain the increased use of SSRI-drugs is the rapidly increasing demand of drugs. Today there are more doctors available in the society. The doctor’s knowledge has increased as well as for parents and teachers when it comes to depression and the drugs that work well against it. As a conclusion to epitomize this report, the prescription of antidepressants has increased due to an overall factor like lifestyle changes and increased knowledge.

Introduktion Selektiva serotoninåterupptagshämmare (SSRI) är idag de mest använda läkemedlen för behandling av depression, både i Sverige och runt om i världen. Studier som gjorts pekar dock på att användning av dessa preparat under graviditet kan medföra vissa risker för fostret. Ett samband har setts mellan moderns exponering för SSRI och ökad risk för persistent pulmonell hypertension hos nyfödda (PPHN). Det är en ovanlig men mycket allvarlig kardiovaskulär sjukdom, där omkring 10-20 % av de barn som drabbas avlider. Trots detta är SSRI ett förstahandsval vid behandling av gravida, då obehandlad depression anses innebära en större risk för såväl kvinna som foster. Syfte Att studera sambandet mellan SSRI och PPHN, och uppskatta hur stor risk som behandling under graviditet innebär. Dessutom undersöks skillnader, vad gäller risk, mellan specifika preparat. Metod Den här litteraturstudien omfattar sju originalstudier där risken för PPHN vid behandling med SSRI har studerats. Sex kohortstudier och en fallkontrollstudie har inkluderats, där fyra av dessa undersökt om tidpunkten för själva exponeringen har någon betydelse. Artikelsökningar har gjorts i databasen PubMed. Resultat Fem av sju studier visade på en signifikant ökad risk för PPHN vid SSRI-behandling under sen graviditet, medan två studier inte fann något samband. Den relativa risken varierade mellan 1.12 - 6.1 i de studier där ett samband påvisats. För behandling under tidig graviditet visade två av fyra studier på ett signifikant samband, med en relativ risk på 2.3 resp. 2.4. Inga stora skillnader mellan specifika preparat kunde påvisas, dock sågs en något högre risk vid behandling med paroxetin, jämfört med övriga SSRI. Diskussion I flera av studierna finns många felkällor, där störfaktorer och bias bidrar till osäkerhet. Studierna har stor variation vad gäller inklusionskriterer, antal deltagare och hantering av eventuella störfaktorer, vilket gör resultaten mer eller mindre tillförlitliga. Slutsats Behandling med SSRI under graviditetens andra hälft tycks vara förknippat med en ökad risk för PPHN. Den låga relativa risken och det faktum att sjukdomen är mycket ovanlig innebär dock att den absoluta risken är väldigt låg. Ett eventuellt samband vid behandling under tidig graviditet kan inte uteslutas. Preparaten sertralin och citolapram är att föredra framför paroxetin.

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Inhibiting peripheral serotonin (5-HT) synthesis has been shown to prevent the development of diet-induced obesity, glucose intolerance, insulin resistance and hepatic lipid deposition and to increase brown adipose tissue (BAT) thermogenic capacity. This thesis investigated 1) what effects 5-HT has on brown adipocytes (BAs), 2) if 5-HT and/or selective serotonin reuptake inhibitors (SSRIs) impair BAT function, 3) if 5-HT directly inhibits BA via a receptor-mediated mechanism, 4) which 5-HT receptor is predominantly expressed in BAT, 5) if 5-HT receptor antagonism improves BAT function and 6) if 5-HT receptor inhibition reduces SSRI induced weight gain. In murine BAs, 5-HT at concentrations ≥100 μM acutely reduced lipolysis, lipid accumulation and glycolytic flux but did not impair oxygen consumption; whereas 10 nM 5-HT reduced Ucp1 promoter activity via an extracellular receptor-mediated mechanism. Acute injection of 5-HT or the selective serotonin reuptake inhibitor (SSRI) Paroxetine decreased BA T thermogenic capacity and energy expenditure (EE), respectively. Mice lacking the serotonin transporter gene (Slc6a4-/- mice) had increased adiposity, decreased locomotor activity and increased food intake. However, male Slc6a4-/- mice had increased BAT thermogenic capacity, in contrast to the reduced EE expenditure following acute administration of Paroxetine. Using, RNA-Seq analysis and measurements of canonical 5-HT receptor second messengers (i.e. Ca2+ and cAMP transients), 5-HT2A was identified as the highest expressed 5-HT receptor in murine and human BAs and the only detected active 5-HT receptor in murine BAs. Genetic elimination of 5-HT2A prevented 5-HT induced increases in Ca2+ transient peaks and decreases in Ppargc1a mRNA expression in cultured BAs. In vivo ablation of 5-HT2A in adipose tissue increased BAT thermogenic capacity. Furthermore, in silico analyses predicted that pharmacological inhibition of 5- HT2A would induce a thermogenic program. In vitro, 5-HT2A receptor antagonists eliminated 5-HT induced Ca2+ transients and in vivo, a single injection of a peripherally-restricted 5-HT2A antagonist (Xylamidine) prevented 5-HT-induced impairments in BAT-mediated EE. Chronic administration of Xylamidine to chow- fed mice for 5-weeks improved BA T thermogenesis. Co-administration of Xylamidine with Paroxetine, however, did not attenuate Paroxetine-induced weight gain but did improve BAT functional capacity Therefore, 5-HT2A antagonism improves BAT thermogenic capacity but does not increase EE. This represents a novel therapeutic approach for increasing thermogenic capacity that may be used in conjunction with BAT activating strategies to increase EE and attenuate obesity. / Thesis / Doctor of Philosophy (PhD) / Obesity is a growing global pandemic caused by excessive energy intake over energy expenditure (EE). Some medications, such as certain selective serotonin (5-HT) reuptake inhibitor (SSRI) type antidepressants, also contribute to weight gain via reasons which are not fully understood. Currently available weight- loss medications decrease energy intake but do not affect EE. Recently, inhibiting the production of 5-HT outside the brain decreased weight gain in a model of obesity. Furthermore, this was associated with an improvement in the activity of a specialized type of adipose tissue, called brown adipose tissue (BAT). BAT is capable of expending energy in the form of thermogenesis and thus when active increases energy expenditure. We hypothesized that 5-HT impairs BAT activity and that blocking 5-HT activity may reduce weight gain in a model of antidepressant- induced weight gain. Herein, we investigated whether elevating 5-HT or increasing 5-HT downstream signaling modified BAT activity, which 5-HT receptor(s) is/are predominantly expressed in brown adipocytes (BAs), and what the effect on BAT would be if this/these receptors were eliminated. We found that in cell culture “supraphysiological” doses of 5-HT acutely impaired BA lipid mobilization and glucose metabolism; whereas, circulating concentrations of 5-HT impaired expression of select mitochondrial genes when serotonin transport was reduced. In mice, acute injections of high dose 5-HT attenuated BAT activity in response to an adrenergic stimulus. Acute treatment with an SSRI decreased EE and locomotor activity. Mice genetically lacking the serotonin transporter (the target of SSRIs) had increased weight gain (particularly fat mass), increased food intake and reduced locomotor activity, but improved BAT functional capacity. We subsequently identified that the predominantly expressed and active receptor in BAs was the 5- HT2A receptor. Genetically eliminating the 5-HT2A receptor in BAs prevented 5- HT’s reduction of a major mitochondrial gene expression regulator and improved BAT functional capacity in mice. Inhibiting 5-HT2A with a 5-HT2A brain impermeable antagonist, Xylamidine, increased BAT functional capacity in mice. Treating mice with Paroxetine (Paxil®), a SSRI known to increase weight gain, and Xylamidine did not attenuate Paroxetine-induced weight gain nor increase EE but did improve BAT functional capacity. In conclusion, we found that 1) chronic treatment with physiological levels of 5-HT impaired BAT functional capacity, 2) elimination/inhibition of adipocyte 5-HT2A improved BAT functional capacity in vivo and 3) inhibiting peripheral 5-HT2A alone did not attenuate Paroxetine- induced weight gain.

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