| 1. |
- Berggård, Cecilia, 1975-
(författare)
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Transcription Factor AP-2 in Relation to Personality and Antidepressant Drugs
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The CNS monoaminergic systems are considered as the head engine regulating neuropsychiatric functions and personality. Transcription factor AP-2 is known to be essential for the development of the brainstem including the monoaminergic nuclei, and has the ability to regulate many genes in the monoaminergic systems. The ability of transcription factors to regulate specific gene expression, has lately made them hot candidates as drug targets. In this thesis, results indicating a role of AP-2 in the molecular effects of the antidepressant drugs citalopram and phenelzine, are presented. A polymorphism in the second intron of the gene encoding AP-2ß has previously been associated with anxiety-related personality traits as estimated by the Karolinska Scales of Personality (KSP). In this thesis, results confirming this association, gained by using a larger material and several different personality scales, are presented. Furthermore, data is presented showing an association between the activity of platelet monoamine oxidase, a trait-dependent marker for personality, and the genotype of the AP-2ß intron 2 polymorphism. The functional importance of the AP-2ß intron 2 polymorphism has not yet been elucidated. Included in this thesis are results showing that the AP-2ß intron 2 polymorphism is not in linkage disequilibrium with the only other described polymorphism in the AP-2ß gene, i.e. in the AP-2ß promoter (-67 G/A). Introns have in several studies been shown to include binding sites for regulatory proteins, and thus, to be important in transcriptional regulation. Results are presented demonstrating that one human brain nuclear protein binds only to the long variant of the AP-2ß intron 2 polymorphism. If this protein is involved in the regulation of the AP-2ß gene, it would affect the expression levels of the AP-2ß protein. In general, this thesis further establishes the role of transcription factor AP-2 as a regulatory factor of importance for personality and monoaminergic functions.
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| 2. |
- Comasco, Erika, 1982-
(författare)
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Alcohol Consumption among Adolescents : Psychosocial and Genetic influences
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The present thesis is based on four studies focusing on alcohol consumption among Swedish adolescents, and therewith related psychosocial and genetic factors. One main objective was to study the reasons for drinking alcohol among different population - representative samples of adolescents in order to identify motives for drinking. Relationships between these drinking motives, alcohol consumption, and alcohol - related problems were also investigated. Three motives emerged from this study: social - enhancement, coping and dominance. The association with alcohol consumption and alcohol - related problems was positive for social - enhancement and coping motives, but negative for the dominance motive. A significant heritability of alcohol use disorders has been demonstrated by family, adoption and twin studies. Environmental influences have also been acknowledged to play an important role in the development of alcohol use disorders. Moreover, the interaction between genetic and environmental factors is likely to influence the risk - resilience for alcohol use disorders. In view of this knowledge, plausible candidate polymorphisms were considered in gene - environment interaction models. An effect of the genetic polymorphisms was only present when a G x E model was considered. A genetic variant of the clock gene Period2, in an interaction with sleep problems, was studied in relation to alcohol consumption among adolescents. High alcohol consumption was associated with the AA genotype of the PER2 SNP10870 polymorphism, in an interaction with several and frequent sleep problems, among adolescent boys. A genetic variant in the opioid µ receptor 1 gene, in an interaction with alcohol consumption, was studied in relation to depressive symptoms. Depressive symptoms were predicted by the G allele of the OPRM1 A118G polymorphism, in an interaction with high alcohol consumption, among adolescent girls. Additionally, the PER2 SNP10870 and the OPRM1 A118G polymorphisms were studied in a sample of severely alcoholic females. Furthermore, alcohol consumption was assessed by using different instruments, such as biomarkers and surveys. Comparisons were carried out to identify the most suitable method to assess alcohol consumption among adolescents. Questionnaire and interview seemed more suitable tools than biomarkers in this regard.The results eventually support the importance of psychosocial and genetic influences, and their interaction effect on alcohol consumption among adolescents.
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| 3. |
- Göktürk, Camilla, 1967-
(författare)
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Semicarbazide-sensitive Amine Oxidase (SSAO) – Regulation and Involvement in Blood Vessel Damage with Special Regard to Diabetes : A Study on Mice Overexpressing Human SSAO
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Semicarbazide-sensitive amine oxidase (SSAO, EC 1.4.3.6) belongs to a family of copper-containing amine oxidases. SSAO exists as a membrane bound protein in endothelial-, smooth muscle-, and adipose cells as well as soluble in plasma. SSAO catalyses oxidative deamination of primary monoamines, which results in the production of corresponding aldehydes, hydrogen peroxide and ammonia. These compounds are very reactive and potentially cytotoxic, and are able to induce vascular damage if produced in high levels. Patients with diabetes mellitus, and with diabetic complications in particular, have a higher SSAO activity in plasma compared to healthy controls. It has therefore been speculated that high SSAO activity is involved in the development of vascular complications associated with diabetes. The aim of this thesis is to investigate the importance of SSAO in the development of disorders of a vascular origin. We have studied the transcriptional regulation of the SSAO gene, by inducing diabetes in NMRI and in transgenic mice, overexpressing the human form of SSAO in smooth muscle cells. We found that the increase in SSAO activity in diabetes is accompanied by reduced mRNA levels of the endogenous mouse gene, suggesting a negative feedback on the transcription of the SSAO gene. In addition, the transgenic mice exhibited an abnormal phenotype in the elastic tissue of aorta and renal artery. These mice have a lower mean artery pressure and an elevated pulse pressure. These results indicate that high SSAO activity in smooth muscle cells is associated with a change in the morphology of large arteries. This is likely contributing to the development of vascular complications in diabetes.
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| 4. |
- Johansson, Jessica, 1977-
(författare)
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Amino acid transport and receptor binding properties in neuropsychiatric disorders using the fibroblast cell model
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Altered transport of the catecholamines and serotonin precursor amino acids tyrosine and tryptophan, might be one explanation for the dysfunctional neurotransmission implicated in the pathophysiology of bipolar disorder and Attention Deficit/Hyperactivity Disorder (ADHD). In previous studies, an altered amino acid transport has been found in schizophrenia and autism, when using the fibroblast cell model. The aim of this thesis was to investigate if the transport of precursor amino acids also may be altered in bipolar disorder and ADHD, and to relate the pre-synaptic activity (transport) with post-synaptic activity (receptors). A functional characterization of tryptophan transport in fibroblasts was also motivated, since the transport of tryptophan in fibroblast cells has not been fully explored. Fibroblast cell lines from patients with bipolar type-1 disorder, from children with ADHD and from controls were included in the studies. The maximal transport capacity (Vmax) and affinity constant (Km) of tyrosine, tryptophan and alanine transport in bipolar patients and ADHD children were determined. Tryptophan transport characterization included; 1) measuring the uptake of tryptophan at high and low concentrations in the presence or absence of transporter selective inhibitors; 2) determination of Vmax and Km of tryptophan transport at high and low concentrations; 3) sodium dependency studies of tryptophan uptake. All transport studies were done using the cluster tray method. Furthermore, the maximal binding capacity (Bmax) and the equilibrium dissociation constant (KD) of muscarinic acetylcholine receptors (mAChRs) were determined in the ADHD children by a radioligand binding assay, using the mAChRs antagonist QNB. In patients with bipolar disorder a decreased Vmax in the transport of tyrosine was observed (p=0.027), while the children with ADHD had a decreased Vmax of tryptophan transport (p=0.039) and an increased Vmax of alanine transport (p=0.031). Children with a hereditary ADHD also had a significantly decreased Bmax (p=0.01). The uptake of tryptophan at both high and low concentrations was partly sodium dependent and the inhibitors had different inhibitory effects on the tryptophan uptake. The uptake of tryptophan at high concentration had low affinity and high Vmax, whilst at low concentration the transport was with high affinity and low Vmax. Altered amino acid transport was observed in fibroblasts of both bipolar disorder patients and ADHD children, which might indicate that the availability of precursor amino acid in the brain is altered. This could lead to disturbances, directly or indirectly, in the catecholaminergic and serotonergic systems. Children with hereditary ADHD might also have reduced levels of mAChRs in the CNS that could indirectly affect the dopaminergic activity. The uptake of tryptophan was through multiple transporters and was different at different substrate concentrations in terms of sodium dependency, affects of inhibitors and kinetic parameters.
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| 5. |
- Karlsson, Krister, 1972-
(författare)
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Substance P Endopeptidase : Purification and Characterizataion of Enzyme Activity and Evaluation of its Function during Stressful Condition
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The purification and biochemical characterization of the substance P (SP) hydrolyzing enzyme, substance P endopeptidase (SPE), have been carried out; with subsequent orientation in neurobiological fundamental processes involved in opioid dependence, withdrawal, and heat-stress.SPE was purified from rat spinal cord, human spinal cord and cerebrospinal fluid (CSF), rat ventral tegemental area (VTA), and rat hippocampus. The enzyme activity was found to release the biologically active fragments SP(1-7) and SP(1-8) as major products. The purified enzymes were characterized with regard to their biochemical and kinetic properties. The typical SPE is neither inhibited by phosphoramidon nor captopril nor phenylmethanesulfonylflourid (PMSF). In comparison to other known proteases SPE differed in characteristics regarding substrate specificity, inhibition-profile, cleavage pattern, and other kinetic parameters. The technically very delicate approach of micro purification of SPE from the rat ventral tegemental area (VTA) (this is a very small tissue), turned out to be possible with the ÄKTA™-purifier system. Studies revealed a crucial role of SPE in a series of clinically important neuropathological conditions, such as opioid tolerance, and withdrawal (SPE, increased); and heat-stress (SPE, increased). These findings emerged from assessment of enzyme activity in hypothalamus, nucleus accumbens (NAc) periaqueductal gray (PAG), pituitary, striatum, substantia nigra (SN), VTA, spinal cord. Viewing the role of SPE in morphine tolerance, it was possible to note regional differences with a decrease in PAG, and striatum, whereas an increase was seen in SN, and VTA. After heat-stress treatment, SPE was raised in several regions (cerebral cortex, hippocampus, diencephalon, cerebellum, spinal cord), and the most precise observation of this was located to the hippocampus structure.
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| 6. |
- Nilsson, Kent W., 1964-
(författare)
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Gene-Environment Interaction in Adolescent Deviant Behaviour
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The overall aim of this thesis was to explore gene-environmental (G*E) interactions in relation to deviant behaviour among 200 Swedish adolescents, with a focus on criminality, alcohol consumption and depressive symptoms. Those behaviours have been extensively investigated in relation to both psychosocial and biological risk factors. The biological markers used were the monoamine oxidase (MAO-A) and serotonin transporter (5-HTTLPR) gene polymorphisms. The main findings indicated a considerable gene-environment interaction in relation to all outcome variables studied. Individuals with the long/short variant of the 5HTTLPR gene, in combination with unfavourable family relations, both consumed more alcohol and had 12-14 times higher risks of being classified as high alcohol consumers. The MAO-A gene showed a G*E interaction related to criminality. Among boys, the short allele predicted an increased risk for criminality, whereas among girls, it was the long allele, if they lived in multi-family houses and/or had been maltreated, assaulted or sexually abused. A G*E interaction in relation to depressive symptoms among both boys and girls was determined. Girls carrying the short 5HTTLPR allele in combination with psychosocial stress, presented elevated depressive symptoms, whereas among boys, the long 5HTTLPR allele was a source of depressive symptoms. In both sexes, there was a G*E interaction of a psychosocial risk index. Girls were more affected by poor family relations and boys by multi-family housing and separated parents. In conclusion, the MAO-A and 5HTTLPR genotypes, in interaction with psychosocial adversity, are related to different deviant behaviours among adolescents. The direct effects of the genotypes needed to be adjusted for the psychosocial factors, whereas the psychosocial factors had direct relation to the outcome measures. There is also an indication of a different pattern in G*E interaction between boys and girls and that different psychosocial factors affect boys and girls differently.
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| 7. |
- Norqvist-Sjöberg, Astrid, 1953-
(författare)
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Amine oxidases in dental pulp : a study with special regard to a semicarbazide-sensitive amine oxidase with catalytic potency towards serotonin
- 1988
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The amine oxidizing capacity of piglet dental pulp tissue has been investigated. At least six separate enzyme activities could be distinguished:- a soluble semicarbazide-sensitive (SSAO) activity towards benzylamine, most likely to be derived from the content of blood plasma within the pulp tissue;- a soluble pulp tissue SSAO activity with most properties in common with the plasma enzyme, however with great efficiency not only regarding benzylamine but also tryptamine;- a tissue bound SSAO activity with activity towards benzylamine, tryptamine, tyramine and ß-phenylethylamine;- a tissue bound semicarbazide-sensitive activity towards serotonin (SSA0-5HT) (a combination of properties never reported before);- a mitochondrially bound and clorgyline-sensitive monoamine oxidase-A (MAO-A) activity with activity towards serotonin;- a mitochondrially bound and deprenyl-sensitive MAO-B activity with activity towards e.g. benzylamine, tryptamine, tyramine and ß-phenylethylamine.The relative importance of the various activities for the metabolism of some monoamines has been investigated.Although the SSAO enzymes had lower K values with most substrates than the MAO, the bulk of ïhe compounds was likely to be metabolized by MAO-B because of higher V values. K values and values with serotonin, howSver,were rather similar for rfle MAO and the SSAO membrane-bound enzyme(s).The thermal sensitivity of membrane-bound SSAO activities was found to be considerably lower than that for MAO-B.The SSAO-5HT activity was found to be localized to the plasma membrane with a greater activity towards the perifery of the pulp tissue than towards the centre.No great difference in the various amine oxidase activities was found when pulp tissues of varying degrees of maturity were compared.The occurrence of membrane-bound SSAO and MAO activities was investigated and compared between pig, ox and human dental pulp. All activities were found to be present in about the same order of magnitude in all three species with the exception of a higher MAO-A activity in the ox pulp and the absence of this enzyme activity in the human dental pulp.
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| 8. |
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| 9. |
- Wargelius, Hanna-Linn
(författare)
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The Relation between Serotonergic Biomarkers and Behaviour : – studies on human primates, non-human primates and transgenic mice
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Rationale: The serotonergic system is involved in the modulation of emotion and plays an important role for personality and vulnerability for psychiatric disorders. In the papers included in this thesis, we investigate three biological factors that have been studied in relation to psychiatric symptoms: Platelet monoamine oxidase B (MAO-B) activity, and variations in the MAO-A and the serotonin transporter (5HTT) genes. We also study intensity dependent auditory evoked potentials (IAEP) as an intermediate phenotype for serotonergic capacity. Platelet MAO-B has been shown to be a biological marker for the properties of monoamine systems, with low activity being associated with vulnerability for high scores of sensation seeking, monotony avoidance, and impulsiveness, as well as for susceptibility for alcoholism. Functional polymorphisms in the promoter of the genes encoding MAO-A and the serotonin transporter result in high- or low- activity alleles that have been associated with numerous psychiatric symptoms. One hypothesis for the shaping of personality is that these genotype variants have prenatal effects on the wiring of the brain. Thus, exploring how the development of the brain is affected by different prenatal serotonin levels is relevant in this context. Observations: (i) Platelet MAOB activity was associated with monoamine metabolites in cerebrospinal fluid from cisterna magna in monkeys, as well as with voluntary alcohol intake, alcohol-induced aggression, and alcohol sensitivity. (ii) The long 5HTTLPR allele was associated with increased IAEP. (iii) The functional MAOA and 5HTT polymorphisms were associated with symptoms of ADHD-related traits in a population based sample of Swedish adolescents. Associations of these candidate genes with ADHD scores were strenghtened when the platelet MAOB activity was combined with genotype. (iv) Our pilot data showed that treatment of pregnant mice with 5HTT blocking antidepressives resulted in more serotonergic cellbodies in lateral wings of dorsal raphe in the offspring, when compared to saline treatment. Conclusions: Our studies support the notion that platelet MAOB activity and IAEP are endophenotypes for monoaminergic capacity and related behaviours. The functional candidate polymorphisms in MAOA and 5HTT were linked to behaviour, however, the cause-relationship is unclear and the explanation for the associations need to be further investigated, possibly with focus on prenatal effects of the polymorphisms.
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| 10. |
- Åslund, Cecilia, 1977-
(författare)
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Depression and Antisocial Behaviour in Adolescents : Influence of Social Status, Shaming, and Gene-Environment Interaction
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis investigated (1) social status and shaming experiences in relation to aggressive behaviour and depression, and (2) gene-environment interactions between two genetic polymorphisms related to the serotonergic system – MAOA-VNTR and 5HTTLPR – and experiences of maltreatment in relation to delinquent behaviour and depression among adolescents. The four included studies are based on questionnaire data from the Survey of Adolescent Life in Vestmanland 2006 (SALVe-2006). A total of 5396 students in 9th (15-16 years old) grade of elementary school and 2nd (17-18 years old) grade of high school comprised the target population. The students in 2nd grade of high school also provided a saliva sample for gene extraction. There were strong associations between shaming experiences and both aggressive behaviour and depression. In addition, individuals who reported many shaming experiences and had either low or high social status had increased risks of physical aggression or depression, whereas medium social status seemed to have a protective effect. Gene-environment interactions were found between experiences of maltreatment and the MAOA-VNTR in relation to delinquent behaviour. Moreover, the direction of the gene-environment interaction differed depending on sex: boys with the short (S) variant of the MAOA-VNTR, in contrast to girls with the long (LL) variant, had the highest risk of delinquency in combination with maltreatment. Gene-environment interactions were also found between experiences of maltreatment and the 5HTTLPR in relation to depression among girls. The girls that were homozygous for the S allele (SS) had the highest risk of depression in combination with maltreatment. Among boys however, no gene-environment interaction was found between the 5HTTLPR and maltreatment in relation to depression. In conclusion, it is important to consider both genetic effects, and psychosocial factors such as social status, shaming experiences, and experiences of maltreatment when investigating different aspects of health and behaviour among adolescents.
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