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  • 1. Abrahamsson, Hasse
    et al.
    Ostlund-Lindqvist, Ann-Margret
    Nilsson, Ralf
    Simren, Magnus
    Gillberg, Per-Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Altered bile acid metabolism in patients with constipation-predominant irritable bowel syndrome and functional constipation2008In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, Vol. 43, no 12, 1483-1488 p.Article in journal (Refereed)
    Abstract [en]

    Objective. Bile acids are derived from cholesterol and are potent physiological laxatives. The aim of this study was to investigate whether bile acid synthesis is altered in constipation. Material and methods. Female patients with constipation (23 IBS-C, 4 functional constipation (FC)) were studied and compared with non-constipated subjects (16 IBS-D, 20 healthy women). Body mass index (BMI), blood lipids, lanosterol, sitosterol, colonic transit (oro-anal transit time (OATT), reference=4.3 days) and stool frequency were measured. C4 (7--hydroxy-4-cholesten-3-one) levels reflecting bile acid synthesis were measured at 0800 h and 1300 h. Results. When all the groups of constipated and non-constipated subjects were compared, it was found that only stool frequency and OATT differed between groups (p 0.001). When constipated patients were categorized according to OATT, absence of the usual C4 increase at lunchtime was noted in 82% of patients with delayed OATT compared with 17% in subjects with normal OATT (p 0.001). Symptom severity did not differ between groups. A subset of the patients with severely delayed OATT had markedly elevated C4 levels. Conclusions. Patients with IBS-C and FC have marked changes in bile acid synthesis in relation to colonic transit. The diurnal rhythm is altered in the slow transit colon when there is no C4 peak at lunchtime. Alterations in bile acid metabolism may be implicated in the pathophysiology of constipation.

  • 2. af Klinteberg, Britt
    et al.
    Alm, Per-Olof
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Serotonin, personality and smoking2000Conference paper (Refereed)
  • 3. Akkermann, Kirsti
    et al.
    Kaasik, Kadri
    Kiive, Evelyn
    Nordquist, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Harro, Jaanus
    The impact of adverse life events and the serotonin transporter gene promoter polymorphism on the development of eating disorder symptoms2012In: Journal of Psychiatric Research, ISSN 0022-3956, E-ISSN 1879-1379, Vol. 46, no 1, 38-43 p.Article in journal (Refereed)
    Abstract [en]

    Adverse life events have been shown to predict weight fluctuations and dietary restraint, as well as eating disorders during adolescence or early adulthood. Since the s-allele carriers of the 5-HTT gene-linked polymorphic region (5-HTTLPR) are biologically more reactive to stress related stimuli, we aimed to explore whether the eating disturbances are predicted by environmental stressors and moderated by the 5-HTTLPR genotype. The sample was based on the younger cohort of the Estonian Children Personality, Behaviour and Health Study and included those participating in its second and third wave. The history of stressful life events was self-reported at age 15. Data on eating behaviour and attitudes, anxiety, impulsivity and depressiveness were collected at age 18. The effect of the adverse life events on binge eating and on drive for thinness was found to be moderated by the 5-HTTLPR. Adolescent girls who at age 15 had reported a history of frequent adverse life events had elevated scores in EDI-2 Bulimia subscale at age 18 if they were carrying the s-allele. The effect of the s-allele on binge eating was even more pronounced when solely the experience of sexual abuse was considered. The interaction effect of the 5-HTTLPR and the past sexual abuse was also observed on drive, for thinness. These data give further support to the idea that adverse life events in childhood may heighten susceptibility to serotonergic dysregulation following stress, and suggest that in individuals vulnerable to eating disorders this may result in disturbed eating behaviours.

  • 4. Akkermann, Kirsti
    et al.
    Nordquist, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Harro, Jaanus
    Serotonin transporter gene promoter polymorphism affects the severity of binge eating in general population2010In: Progress in Neuro-psychopharmacology and Biological Psychiatry, ISSN 0278-5846, E-ISSN 1878-4216, Vol. 34, no 1, 111-114 p.Article, review/survey (Refereed)
    Abstract [en]

    Objective: The s-allele of the 5-HTTLPR has been suggested to lead to the development of less efficient and less flexible 5-HT system and has been associated to different forms of psychopathology. It has also been shown that alterations in serotonergic activity contribute to the pathophysiology of binge eating but it is not clear which changes in 5-HT function observed in eating disorder patients represent trait vs state effect. We investigated the association between the 5-HTTLPR and binge eating in a population-representative sample of women, and tested whether the 5-HTTLPR genotype influences the severity of binge eating. Methods: The sample was based on women participating in the third wave of the Estonian Children Personality, Behaviour and Health Study. EDI-2 subscales - drive for thinness and bulimia - were used to assess eating behaviour and attitudes. Barratt Impulsiveness Scale (BIS-11) and State and Trait Anxiety Inventory (STAI) were used to measure impulsivity and anxiety. Participants were genotyped for the 5-HTTLPR. Results: There was no 5-HTTLPR genotype effect on binge eating even after the covarying effect of impulsivity and anxiety was controlled for. However, women prone to binge eating and carrying the s-allele showed significantly higher levels of bulimia scores, and among them, women with s/s genotype had also higher levels of state anxiety and tendency for higher impulsivity. Conclusions: While the 5-HTTLPR genotype does not predict symptoms of eating disorder in general population, the s-allele, and especially the s/s genotype increases the risk for affective instability and symptom severity.

  • 5. Akkermann, Kirsti
    et al.
    Paaver, Marika
    Nordquist, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Harro, Jaanus
    Association of 5-HTT gene polymorphism, platelet MAO activity, and drive for thinness in a population-based sample of adolescent girls2008In: International Journal of Eating Disorders, ISSN 0276-3478, E-ISSN 1098-108X, Vol. 41, no 5, 399-404 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Several lines of evidence suggest that alterations in serotonergic activity contribute to the pathophysiology of abnormal eating behaviors. Since platelet monoamine oxidase (MAO) activity and the 5-HT transporter gene promoter polymorphism (5-HTTLPR) have been associated with eating disorders, the knowledge from a population-based sample may provide useful information which changes in 5-HT function observed in eating disorders represent trait vs. state effects. METHOD: The sample was based on both cohorts of the Estonian Children Personality, Behavior and Health Study (ECPBHS). The current study was conducted during the second follow-up where altogether 82% from the original sample was recruited. EDI-2 subscales--Drive for Thinness and Bulimia--were used to determine eating attitudes and behaviors. Platelet MAO activity was measured and the participants were genotyped for the 5-HTTLPR. RESULTS: Allelic variation of 5-HTTLPR or platelet MAO activity were not independently associated with drive for thinness or binge eating, but girls homozygous for the 5-HTTLPR long allele and with high platelet MAO activity, both considered indicators of a higher capacity 5-HT system, exhibited higher scores of drive for thinness. CONCLUSION: The results suggest that drive for thinness is the highest in girls with the presence of two markers of higher serotonergic capacity.

  • 6.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Olszewski, Pawel K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jonsson, Petra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Levine, Allen S.
    Minnesota Obesity Center, VA Medical Center, Minneapolis, MN, USA.
    Meyerson, Bengt J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Hulting, Anna-Lena
    Department of Endocrinology, Metabolism and Diabetology, Karolinska Institutet, Stockholm.
    Lindblom, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Inverse association of high-fat diet preference and anxiety-like behavior: a putative role for urocortin 22009In: Genes, Brain and Behavior, ISSN 1601-1848, E-ISSN 1601-183X, Vol. 8, no 2, 193-202 p.Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate whether the preference for a palatable high-fat diet (HFD) is associated with response to novelty and with anxiety-like behavior in rats and whether such fat preference correlates with gene expression of hypothalamic neuropeptides related to feeding. We subjected male rats to two tests of exploration of novel environments: the multivariate concentric square field (MCSF) and the elevated plus maze (EPM). The rats were then exposed to a 5-day test of preference for a palatable HFD versus reference diets. Messenger RNA (mRNA) levels of 21 neuropeptides were investigated by quantitative polymerase chain reaction. We found a strong positive correlation of HFD preference and open-arm activity in the EPM (% open-arm time, r(s) = 0.629, df = 26, P < 0.001). Thus, HFD preference was inversely associated with anxiety-like behavior. The same association was found for HFD preference and behavior in the MCSF (bridge entries, r(s) = 0.399, df = 23, P = 0.048). In addition, the HFD preference was positively correlated (r(s) = 0.433, df = 25, P = 0.021) with hypothalamic mRNA levels of urocortin 2 (Ucn 2). Moreover, behavior in the EPM was significantly correlated with expression levels of the receptor for Ucn 2, the corticotropin-releasing factor receptor 2, in the hypothalamus (r(s) = 0.382, df = 33, P = 0.022, pituitary (r(s) = 0.494, df = 31, P = 0.004) and amygdala (r(s) = 0.381, df = 30, P = 0.032). We conclude that preference for palatable HFD is inversely associated with anxiety and propose that Ucn 2 signaling may play a role in this association.

  • 7. Bajor, Antal
    et al.
    Gillberg, Per-Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Abrahamsson, Hasse
    Bile acids: short and long term effects in the intestine2010In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, Vol. 45, no 6, 645-664 p.Article, review/survey (Refereed)
    Abstract [en]

    Bile acids have secretory, motility and antimicrobial effects in the intestine. In patients with bile acid malabsorption the amount of primary bile acids in the colon is increased compared to healthy controls. Deoxycholic acid is affecting the intestinal smooth muscle activity. Chenodeoxycholic acid has the highest potency to affect intestinal secretion. Litocholic acid has little effect in the lumen of intestine compared to both deoxycholic acid and chenodeoxycholic acid. There is no firm evidence that clinically relevant concentrations of bile acids induce colon cancer. Alterations in bile acid metabolism may be involved in the pathophysiology of constipation.

  • 8.
    Basti, Vida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ligand biased signaling of opioid agonists forphosphorylation and regulation of μ -opioid receptors2013Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Abstract

    Ligand biased signaling of opioid agonists for phosphorylation andregulation of μ -opioid receptors

    Student: Vida Basti.

    Supervisor: Prof Macdonald Christie. Departmement of Neuropharmacology, The University of Sydney.

    Examiner: Prof Ingrid Nylander. Departement of Phamacology, University of Uppsala.

    Opioid drugs are of great use in the medical practise. The drugs are commonly prescribed formany types of illnesses, mostly in cases of pain management. Although opioids come withmany benefits they are causing a lot of problems as well. The side effects are many andamongst these is tolerance development which may lead to abuse and addiction. Because ofthe fast tolerance development in patients, higher doses up to 10 times the therapeutic doseare being prescribed. This is a major issue in today’s society and must be addressed.Scientists are trying to figure out the mechanism behind tolerance by comparing differenttypes opioid drugs. Some opioids causes tolerance in a much faster rate than others but it isstill uncertain why and what is causing this. Two of the most commonly prescribed opioidsare oxycodone and morphine and so in this rapport these opioids are compared with respectto their capability to cause internalization in neurons. In the experiments a positive control,DAMGO, is being used as well as a negative control. The method being used is an indirectmethod of immunohistochemistry on AtT20 transfected cell culture. The results show thatOxycodone seems to cause no internalization at all in comparison to the control.

  • 9.
    Berggard, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Damberg, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Research and Development, Gävleborg.
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Brainstem levels of transcription factor AP-2 in rat are changed after treatment with phenelzine, but not with citalopram2005In: BMC Pharmacology, ISSN 1471-2210, Vol. 5, 1- p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Before therapeutic effect is obtained after treatment with antidepressant drugs, like serotonin selective reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAO-Is) there is an initial lag-period of a few weeks. Neuronal adaptations on a molecular level are supposed to be involved in the initiation of the antidepressant effect. Transcription factor AP-2 is essential for neuronal development and many genes involved in the brainstem monoaminergic systems have binding sites for AP-2 in their regulatory regions. The genotype of the AP-2beta isoform has been associated with e.g. anxiety-related personality traits and with platelet MAO activity. In addition, previous studies have shown that the levels of AP-2alpha and AP-2beta in rat whole brain were decreased after 10 days of treatment with citalopram (SSRI) and imipramine (TCA), and were increased with phenelzine (MAO-I). RESULTS: In the present study, we report that treatment with citalopram for 1, 7 or 21 days did not have effect on the AP-2 levels in rat brainstem. However, after treatment with phenelzine for 1, 7 or 21 days the levels of AP-2alpha and AP-2beta had increased after 7 days, but had returned to control levels at day 21. CONCLUSION: The decrease in AP-2 levels in rat whole brain previously seen after treatment with citalopram does not seem to be localised to the brainstem, it may rather occur in the monoaminergic terminal projection areas. The present data suggest that the increase in AP-2 levels previously seen in rat whole brain after subchronic treatment with phenelzine is located in the brainstem. It cannot, however, be excluded that other brain regions are involved.

  • 10.
    Birgner, Carolina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology.
    Kindlundh-Högberg, Anna M. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Bergström, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology.
    Altered extracellular levels of DOPAC and HVA in the rat nucleus accumbens shell in response to sub-chronic nandrolone administration and a subsequent amphetamine challenge2007In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 412, no 2, 168-172 p.Article in journal (Refereed)
    Abstract [en]

    Associated with acts of violence and polydrug use, abuse of anabolic androgenic steroids (AAS) is an increasing problem in society. The aim of the present study was to elucidate whether sub-chronic treatment with the AAS nandrolone decanoate affects dopamine release and dopamine metabolism in the rat nucleus accumbens shell, before and after an amphetamine challenge. Male Sprague–Dawley rats received daily i.m. injections of nandrolone decanoate (15 mg/kg) or vehicle for 14 days. On day 15, the animals were anaesthetized and a microdialysis probe was implanted into the nucleus accumbens shell. Extracellular fluid was collected 1 h before and 3 h after a single amphetamine injection (5 mg/kg). The samples were then analyzed regarding the content of dopamine, and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), using HPLC with electrochemical detection. Two weeks of nandrolone decanoate administration caused a significant decrease of the basal DOPAC and HVA levels, which remained low during the first hour following the amphetamine challenge. Dopamine levels did not differ significantly between groups, neither after the nandrolone pre-treatment nor the amphetamine challenge. In conclusion, these novel findings indicate that AAS alter the metabolism of dopamine in a brain region involved in the development of drug dependence.

  • 11.
    Birgner, Carolina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology.
    Kindlundh-Högberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Alsiö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lindblom, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Bergström, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Reduced activity of monoamine oxidase in the rat brain following repeated nandrolone decanoate administration2008In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1219, 103-110 p.Article in journal (Refereed)
    Abstract [en]

    Anabolic androgenic steroids (AAS) are known as doping agents within sports and body-building, but are currently also abused by other groups in society in order to promote increased courage and aggression. We previously showed that 14 days of daily intramuscular injections of the AAS nandrolone decanoate (15 mg/kg) reduced the extracellular levels of the dopaminergic metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens shell using microdialysis. The aim of the present study was to investigate whether the same dose regimen of nandrolone decanoate may affect the activities of the dopamine-metabolizing enzymes monoamine oxidases A and B (MAO-A and MAO-B). A radiometric assay was used to determine the activities of MAO-A and MAO-B in rat brain tissues after 14 days of daily i.m. nandrolone decanoate injections at the doses 3 and 15 mg/kg. Gene transcript contents of MAO-A, MAO-B and cathecol-O-methyltransferase (COMT) were measured with quantitative real-time reverse transcription PCR. 3 mg/kg of nandrolone decanoate significantly reduced the activity of both MAO-A and -B in the caudate putamen. 15 mg/kg of nandrolone decanoate significantly reduced the activity of MAO-A in the amygdala and increased the gene transcript level of MAO-B in the substantia nigra. In conclusion, imbalanced MAO activities may contribute to explain the impulsive and aggressive behaviour often described in AAS abusers. The reduced MAO activities observed are in line with our previously presented findings of decreased extracellular levels of DOPAC and HVA in the rat brain, indicating decreased monoaminergic activity following repeated AAS administration.

  • 12.
    Birgner, Carolina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Nordenankar, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Lundblad, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Mendez, José Alfredo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Smith, Casey
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    le Grevés, Madeleine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Galter, Dagmar
    Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Olson, Lars
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, Ulleråker, University Hospital.
    Trudeau, Louis-Eric
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Wallén-Mackenzie, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    VGLUT2 in dopamine neurons is required for psychostimulant-induced behavioural activation2010In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, no 1, 389-394 p.Article in journal (Refereed)
    Abstract [en]

    The “One neuron-one neurotransmitter” concept has been challenged frequently during the last three decades, and the coexistence of neurotransmitters in individual neurons is now regarded as a common phenomenon. The functional significance of neurotransmitter coexistence is, however, less well understood. Several studies have shown that a subpopulation of dopamine (DA) neurons in the ventral tegmental area (VTA) expresses the vesicular glutamate transporter 2 (VGLUT2) and has been suggested to use glutamate as a cotransmitter. The VTA dopamine neurons project to limbic structures including the nucleus accumbens, and are involved in mediating the motivational and locomotor activating effects of psychostimulants. To determine the functional role of glutamate cotransmission by these neurons, we deleted VGLUT2 in DA neurons by using a conditional gene-targeting approach in mice. A DAT-Cre/Vglut2Lox mouse line (Vglut2f/f;DAT-Cre mice) was produced and analyzed by in vivo amperometry as well as by several behavioral paradigms. Although basal motor function was normal in the Vglut2f/f;DAT-Cre mice, their risk-taking behavior was altered. Interestingly, in both home-cage and novel environments, the gene targeted mice showed a greatly blunted locomotor response to the psychostimulant amphetamine, which acts via the midbrain DA system. Our results show that VGLUT2 expression in DA neurons is required for normal emotional reactivity as well as for psychostimulant-mediated behavioral activation.

  • 13. Blomgren, Bo
    et al.
    Göktürk, Camilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    A novel method for quantification of the folding of elastic laminae in elastic arteries2008In: Micron, ISSN 0968-4328, E-ISSN 1878-4291, Vol. 39, no 5, 623-630 p.Article, review/survey (Refereed)
    Abstract [en]

    A transgenic mouse overexpressing the human form of semicarbazide-sensitive amine oxidase (SSAO) is known to have an abnormal structure of the elastic laminae and the elastic fibres in the aorta. Compared to the non-transgenic littermates, the elastic laminae are less folded. In order to quantify the undulation of this structure, an image analysis program that identified the elastic laminae was developed. The program measures the area fraction in different sectors from a plane parallel to the aorta wall. Images were taken from unstained aorta specimens where the elastic laminae were visualised with phase contrast microscopy. A contextual operation of the images produced a local orientation estimation for every linear structure. The image was then thresholded in eight sectors from 0 degrees to 180 degrees, with different orientation angles. The results show that the area fraction of the elastic laminae was significantly lower for the transgenic mouse in all sectors measured except for two. At 0-25 degrees, no difference was seen. In the sector at 160-180 degrees, parallel to the aorta wall, the area fraction of elastic laminae was instead significantly higher in the transgenic mouse. A novel method is presented, developed for detection and quantification of pathological changes in the elastic laminae in the aorta wall. The method gave reliable results and is considered to be a useful tool for morphometric studies of aorta with this kind of altered morphology concerning the elastic laminae. When compared with tangent count, the control group had a significantly larger mean curvature.

  • 14.
    Blomkvist, Josefin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Taube, Adam
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Information Science, Statistics.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Perspective on Roseroot (Rhodiola rosea) Studies2009In: Planta Medica, ISSN 0032-0943, Vol. 75, no 11, 1187-1190 p.Article in journal (Refereed)
    Abstract [en]

    Rhodiola rosea (roseroot) extract is a commercially successful product, primarily used to reduce the effect of fatigue on physical and mental performance. In this perspective we present our investigation of the most recent studies performed on human subjects. With a focus on the statistical methods we found considerable shortcomings in all but one of the studies that claim significant improvement from roseroot extract. Overall, the study designs have not been well explained. Experimental results have been confused and appear to be in some cases incorrect. Some of the conclusions are based on selected results and contradicting data have not been adequately taken into account. We point to other studies of higher quality performed on roseroot, several that found no significant effect and one that did. We conclude that the currently available evidence for the claimed effects is insufficient and that the effect of Rhodiola rosea is in need of further investigation before therapeutic claims can be made.

  • 15.
    Boström, Adrian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Ciuculete, Diana-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Attwood, Misty M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Krattinger, Regina
    Univ Zurich, Univ Zurich Hosp, Dept Clin Pharmacol & Toxicol, Zurich, Switzerland..
    Nikontovic, Lamia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Titova, Olga E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kullak-Ublick, Gerd A.
    Univ Zurich, Univ Zurich Hosp, Dept Clin Pharmacol & Toxicol, Zurich, Switzerland..
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    A MIR4646 associated methylation locus is hypomethylated in adolescent depression2017In: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 220, 117-128 p.Article in journal (Refereed)
    Abstract [en]

    Background: Studies of epigenetics and transcriptional activity in adolescents may provide knowledge about possible preventive strategies of depression. Methods: We present a methylome-wide association study (MWAS) and cohort validation analysis of depression in adolescents, in two separate cohorts: discovery (n = 93) and validation data set 1 (n = 78). The genome-wide methylation pattern was measured from whole blood using the Illumina 450K array. A second validation cohort, validation data set 2, consists of post-mortem brain biopsies from depressed adults (n = 58). We performed a MWAS by robust multiple linear regressions of methylation to a modified risk-score assessment of depression. Methylation levels of candidate CpG sites were correlated with expression levels of the associated gene in an independent cohort of 11 healthy volunteers. Results: The methylation state of two CpG sites reliably predicted ratings of depression in adolescents (cg13227623 and cg04102384) (p < 10E-06). Cohort validation analysis confirmed cg04102384 - located in the promoter region of microRNA 4646 (MIR4646) - to be hypomethylated in both validation data set 1 and validation data set 2 (p < 0.05). Cg04102384 was inversely correlated to expression levels of MIR4646-3p in healthy controls (p < 0.05). Limitations: MIR4646 was not differentially expressed in a subset of samples with adolescent depression measured by qRT-PCR measurements. Conclusion: We identify a specific MIR4646 associated epigenetic risk site to be associated with depression in adolescents. Cg04102384 putatively regulates gene expression of MIR4646-3p. Target gene prediction and gene set overrepresentation analysis revealed involvement of this miRNA in fatty acid elongation, a process related to omega-3 fatty acids, previously associated with depression.

  • 16.
    Bromée, Torun
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Venkatesh, Byrappa
    Brenner, Sidney
    Postlethwait, John H.
    Yan, Yi-Lin
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Uneven Evolutionary Rates of Bradykinin B1 and B2 Receptors in Vertebrate Lineages2006In: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 373, 100-108 p.Article in journal (Refereed)
    Abstract [en]

    Bradykinin acts through two receptor subtypes in mammals and generates a variety of responses including pain, inflammation and hypotension. The evolutionary history of the bradykinin system has been unclear due to shortage of information outside mammals. We describe here two receptor subtypes and the bradykinin precursor in three species of bony fish (the zebrafish Danio rerio, the Japanese pufferfish Takifugu rubripes, and the green spotted pufferfish Tetraodon nigroviridis) and chicken and analyze the relationships to mammals by a combination of phylogeny, conserved synteny and exon–intron organization. All of these species have two receptor genes located close to each other in a tandem formation, with the B2 gene 5′ to the B1 gene, in chromosomal regions displaying conserved synteny between the species (albeit conservation of synteny in zebrafish is still unclear due to poor genome assembly). The evolutionary rate differs between the two genes as well as between lineages leading to differing pharmacological properties for both B1 and B2 across vertebrate classes. Also the bradykinin precursor gene was identified in all of these species in a chromosome region with conserved synteny. The tissue distribution of mRNA in T. rubripes is similar for B1 and B2, suggesting more similar regulation for the two genes than in mammals. In conclusion, the receptor tandem duplication predates the divergence of ray-finned fish and tetrapods and no additional duplicates of the receptors or bradykinin seem to have survived the ray-finned fish tetraploidization.

  • 17. Camras, C. B.
    et al.
    Sharif, N. A.
    Wax, M. B.
    Stjernschantz, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Bimatoprost, the prodrug of a prostaglandin analogue2008In: British Journal of Ophthalmology, ISSN 0007-1161, E-ISSN 1468-2079, Vol. 92, no 6, 862-863 p.Article in journal (Refereed)
  • 18.
    Cardoso, Joao C. R.
    et al.
    Univ Algarve, Ctr Marine Sci, Comparat Endocrinol & Integrat Biol, Campus Gambelas, Faro, Portugal..
    Bergqvist, Christina A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Felix, Rute C.
    Univ Algarve, Ctr Marine Sci, Comparat Endocrinol & Integrat Biol, Campus Gambelas, Faro, Portugal..
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Corticotropin-releasing hormone family evolution: five ancestral genes remain in some lineages2016In: Journal of Molecular Endocrinology, ISSN 0952-5041, E-ISSN 1479-6813, Vol. 57, no 1, 73-86 p.Article in journal (Refereed)
    Abstract [en]

    The evolution of the peptide family consisting of corticotropin-releasing hormone ( CRH) and the three urocortins ( UCN1-3) has been puzzling due to uneven evolutionary rates. Distinct gene duplication scenarios have been proposed in relation to the two basal rounds of vertebrate genome doubling ( 2R) and the teleost fish-specific genome doubling ( 3R). By analyses of sequences and chromosomal regions, including many neighboring gene families, we show here that the vertebrate progenitor had two peptide genes that served as the founders of separate subfamilies. Then, 2R resulted in a total of five members: one subfamily consists of CRH1, CRH2, and UCN1. The other subfamily contains UCN2 and UCN3. All five peptide genes are present in the slowly evolving genomes of the coelacanth Latimeria chalumnae ( a lobe-finned fish), the spotted gar Lepisosteus oculatus ( a basal ray-finned fish), and the elephant shark Callorhinchus milii ( a cartilaginous fish). The CRH2 gene has been lost independently in placental mammals and in teleost fish, but is present in birds ( except chicken), anole lizard, and the nonplacental mammals platypus and opossum. Teleost 3R resulted in an additional surviving duplicate only for crh1 in some teleosts including zebrafish ( crh1a and crh1b). We have previously reported that the two vertebrate CRH/UCN receptors arose in 2R and that CRHR1 was duplicated in 3R. Thus, we can now conclude that this peptide-receptor system was quite complex in the ancestor of the jawed vertebrates with five CRH/UCN peptides and two receptors, and that crh and crhr1 were duplicated in the teleost fish tetraploidization.

  • 19. Cardoso, Joao C. R.
    et al.
    Larhammar, Dan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Comparative evolution of peptide hormone-binding GPCRs: A route to understanding functional complexity2014In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 209, no SI, 1-2 p.Article in journal (Other academic)
  • 20.
    Cardoso, João C R
    et al.
    University of Algarve, Portugal.
    Félix, Rute C
    University of Algarve, Portugal.
    Bergqvist, Christina A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    New insights into the evolution of vertebrate CRH (corticotropin-releasing hormone) and invertebrate DH44 (diuretic hormone 44) receptors in metazoans2014In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 209, no SI, 162-170 p.Article in journal (Refereed)
    Abstract [en]

    The corticotropin releasing hormone receptors (CRHR) and the arthropod diuretic hormone 44 receptors (DH44R) are structurally and functionally related members of the G protein-coupled receptors (GPCR) of the secretin-like receptor superfamily. We show here that they derive from a bilaterian predecessor. In protostomes, the receptor became DH44R that has been identified and functionally characterised in several arthropods but the gene seems to be absent from nematode genomes. Duplicate DH44R genes (DH44 R1 and DH44R2) have been described in some arthropods resulting from lineage-specific duplications. Recently, CRHR-DH44R-like receptors have been identified in the genomes of some lophotrochozoans (molluscs, which have a lineage-specific gene duplication, and annelids) as well as representatives of early diverging deuterostomes. Vertebrates have previously been reported to have two CRHR receptors that were named CRHR1 and CRHR2. To resolve their origin we have analysed recently assembled genomes from representatives of early vertebrate divergencies including elephant shark, spotted gar and coelacanth. We show here by analysis of synteny conservation that the two CRHR genes arose from a common ancestral gene in the early vertebrate tetraploidizations (2R) approximately 500 million years ago. Subsequently, the teleost-specific tetraploidization (3R) resulted in a duplicate of CRHR1 that has been lost in some teleost lineages. These results help distinguish orthology and paralogy relationships and will allow studies of functional conservation and changes during evolution of the individual members of the receptor family and their multiple native peptide agonists.

  • 21. Carlini, Valeria P.
    et al.
    Gaydou, Romina C.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    de Barioglio, Susana R.
    Selective serotonin reuptake inhibitor (fluoxetine) decreases the effects of ghrelin on memory retention and food intake2007In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 140, no 1-2, 65-73 p.Article in journal (Refereed)
    Abstract [en]

    Ghrelin (Ghr) is an appetite stimulating hormone that is produced peripherally, by the stomach, and centrally as well. Previous investigations show that Ghr increases food intake and memory retention in rats, and that extra-hypothalamic structures, such as the hippocampus, participate in these effects. In the present work we analyzed the effect on food intake and memory retention induced by Ghr after serotonin (5-HT) availability modification at the serotoninergic synapses. Animals only treated with a selective serotonin reuptake inhibitor (SSRI), fluoxetine (FLU) 5 mg/kg or clomipramine (CLO) 2.5 and 5 mg/kg, showed a significant reduction in both food intake and memory retention. On the contrary, Ghr administration induces a significant increase in food intake and a dose-dependent increase in short and long term memory retention. When the animals were treated with FLU prior to Ghr injection, the food intake induced, as well as the expression of short and long term memory retention, was decreased. In conclusion, evidence presented in this paper suggests that the effects of Ghr on both feeding and memory retention in extra-hypothalamic structures such as the hippocampus, could depend on the availability of 5-HT.

  • 22. Carlini, Valeria P.
    et al.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Barioglio, Susana R.
    Melanin-concentrating hormone (MCH) reverts the behavioral effects induced by inescapable stress2006In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 27, no 9, 2300-2306 p.Article in journal (Refereed)
    Abstract [en]

    The aim of this work was to investigate if MCH modifies the feeding and freezing responses in rats exposed to stressful stimuli. We used a basic version of contextual fear, where one group of rats were placed in a novel environment and two different groups were exposed to footshock paradigms, one of them escapable and the other one inescapable. At the end of each treatment, freezing and feeding were measured. Only the animals exposed to inescapable footshock paradigm showed significant increase in the food intake and freezing behavior in comparison to the control animals. The MCH administration (intra-hippocampal or intra-amygdaline) reverted these effects elicited by inescapable footshock. Results presented in this paper lead us to the assumption that the anxiolytic effect of the peptide is responsible for the reversion of the IS effects.

  • 23. Carlini, Valeria P.
    et al.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Debarioglio, Susana R.
    Obestatin improves memory performance and causes anxiolytic effects in rats2007In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 352, no 4, 907-912 p.Article in journal (Refereed)
    Abstract [en]

    Obestatin is a peptide hormone that is derived from the same polypeptide precursor (preprogrelin) as ghrelin, but it acts in opposing way on ingestive behavior. Our previous studies showed that ghrelin affects memory and anxiety. Here, we studied the possible effects of icv obestatin injection in rats upon memory retention (using two different paradigms), anxiety like behavior (plus maze test), and food intake. Obestatin induces an increase in the percentage of open arms entries (Obestatin 3.0 nmol/rat: 61.74 ± 1.81), and percentage of time spent in open arms (Obestatin 3.0 nmol/rat: 72.07 ± 4.21) in relation to the control (33.31 ± 1.54; 25.82 ± 1.68), indicating an anxiolytic effect. The two doses of obestatin increased latency time in a step down test and the percentage time of novel object exploration, suggesting that the peptide influences learning and memory processes that involve the hippocampus and the amygdala. This report provides evidence indicating that obestatin effects are functionally opposite on anxiety and hunger to the ghrelin effects, while both these related peptides increase memory retention.

  • 24.
    Comasco, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Berglund, Kenneth
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Nilsson, Kent W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Why Do Adolescents Drink?: Motivational Patterns Related to Alcohol Consumption and Alcohol-Related Problems2010In: Substance Use & Misuse, ISSN 1082-6084, E-ISSN 1532-2491, Vol. 45, no 10, 1589-1604 p.Article in journal (Refereed)
    Abstract [en]

    The present study was designed to investigate motivational patterns for drinking alcohol and their relation about alcohol consumption and problems related to alcohol consumption. Data were collected by semistructured interviews and questionnaires, containing questions about reasons for drinking, alcohol consumption, and problems related to alcohol consumption during the years 2001, 2004, and 2005. Three independent population samples from two different counties of central Sweden were included. A total of 11,167 adolescents participated. Data on reasons for drinking were analyzed by factor analysis to extract components explaining drinking motives. Relationships between motivational patterns and alcohol use were examined with correlation analysis. Three drinking motives emerged (social-enhancement, coping, and dominance motives) and related to alcohol consumption and problems related to alcohol consumption. Limitations of the study are noted and discussed.

  • 25.
    Comasco, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Hellgren, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Sundström-Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Influence of COMT val158met polymorphism on startle response during pregnancy2012In: European psychiatry, ISSN 0924-9338, Vol. 27, no S1Article in journal (Other academic)
  • 26.
    Comasco, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Nordquist, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Göktürk, Camilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Åslund, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Hallman, Jarmila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Nilsson, Kent W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    The clock gene PER2 and sleep problems: association with alcohol consumption among Swedish adolescents2010In: Uppsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 115, no 1, 41-48 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Alcohol abuse is associated with sleep problems, which are often linked to circadian rhythm disturbances. Previous studies have separately examined the effects of mutations in the clock gene PER2 on alcohol consumption and sleep problems. Here we hypothesized that an allelic variation in the PER2 gene is associated with alcohol consumption in interaction with sleep problems among adolescents. METHODS: The Survey of Adolescent Life and Health in Västmanland 2006, a Swedish county, including 1254 students 17-18 years old, was used as a population-representative sample of adolescents. We investigated the PER2 Single Nucleotide polymorphism (SNP) 10870 (A/G) in the cohort together with an assessment of alcohol consumption according to the AUDIT-C questionnaire, and sleep problems using a survey consisting of 18 items. Furthermore, we carried out an exploratory analysis on the PER2 Single Nucleotide Polymorphism 10870 polymorphism in a group of severely alcoholic females. RESULTS: We found a significant association of the SNP 10870 in adolescent boys, where the genotype AA, in the presence of several and frequent sleep problems, was associated with increased alcohol consumption. Among adolescent girls, only sleep problems were related to alcohol consumption. A non-significant trend was observed among the severely alcoholic females, with the G allele being over-represented in the severely alcoholic females group in comparision to the control females. CONCLUSION: These results indicate that PER2 gene variation is associated with alcohol consumption in interaction with sleep problems among Swedish adolescent boys.

  • 27.
    Comasco, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Sylvén, Sara M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Papadopoulos, Fotios C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Sundström-Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Skalkidou, Alkistis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Postpartum depressive symptoms and the BDNF Val66Met functional polymorphism: effect of season of delivery:  2011In: Archives of Women's Mental Health, ISSN 1434-1816, E-ISSN 1435-1102, Vol. 14, no 6, 453-463 p.Article in journal (Refereed)
    Abstract [en]

    Postpartum depression (PPD) is an often underdiagnosed and undertreated mood disorder, with negative impact on the mother's and infant's health. Seasonal variation has been discussed as a risk factor for PPD. Candidate genes, such as those encoding for the brain-derived neurotrophic factor (BDNF), serotonin transporter (5-HTT), and Period2 (PER2), have been associated with depression and seasonal disorders. The present study is aimed to examine whether functional polymorphic variants, BDNF Val66Met, 5-HTTLPR, or PER2 SNP 10870, are associated with PPD symptoms and whether these genetic polymorphisms interact with season in predicting PPD symptoms. This case-control study comprised of 275 women from a population-based cohort of delivering women in Sweden, who completed a questionnaire containing the Edinburgh postnatal depression scale (EPDS) at 6 weeks and 6 months postpartum. Stressful life events (SLEs) and maternity stressors were also assessed. The results did not reveal any statistically significant overall association between the studied genetic polymorphisms and PPD symptoms. However, a significant association between BDNF Met66 carrier status and development of PPD symptoms at 6 weeks postpartum, even when controlling for prepartum and postpartum environmental risk factors, was evident among mothers delivering during autumn/winter. No gene-gene interactions were found but a cumulative effect was detected with carriers of a greater number of 5-HTTLPR S and BDNFVal66Met Met alleles reporting higher EPDS scores, if delivered during autumn/winter. Our findings propose a role of the BDNF gene in the development of PPD symptoms, potentially mediated by season of delivery.

  • 28.
    Comasco, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Sylvén, Sara M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Papadopoulos, Fotios C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Sundström-Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Skalkidou, Alkistis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Postpartum depression symptoms: a case-control study on monoaminergic functional polymorphisms and environmental stressors2011In: Psychiatric Genetics, ISSN 0955-8829, E-ISSN 1473-5873, Vol. 21, no 1, 19-28 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    Postpartum depression (PPD) is an under diagnosed and under treated mood disorder, with negative impact on both the mother and the infant's health. The aim of this study is to examine whether genetic variations in the monoaminergic neurotransmitter system, together with environmental stressors, contribute to the development of PPD symptoms.

    METHODS:

    This nested case-control study included 275 women from a population-based cohort of delivering women in Sweden. A questionnaire containing the Edinburgh Postnatal Depression Scale was collected at 6 weeks and 6 months postpartum. Three functional polymorphisms were genotyped, catechol-O-methyltransferase (COMT)-ValMet, monoamine oxidase A (MAOA)-upstream variable number tandem repeat (uVNTR) and serotonin transporter linked polymorphic region (5HTT-LPR). Stressful life events, maternity stressors and previous psychiatric contact were considered as potential risk factors.

    RESULTS:

    COMT-ValMet was significantly associated with PPD symptoms at 6 weeks, but not at 6 months postpartum. A significant gene-gene interaction effect was present between COMT-ValMet and MAOA-uVNTR. In a gene-environment multivariate model, COMT-ValMet, psychiatric contact and maternity stressors were significantly associated with PPD symptoms. Among those with history of psychiatric problems, the COMT-ValMet and 5HTT-LPR risk variants were associated with PPD symptoms, whereas in the absence of previous psychiatric contact only maternity stressors were related to PPD symptoms.

    CONCLUSION:

    The interaction effect between monoaminergic genes and environmental stressors is likely to contribute to vulnerability for PPD. The different patterns of association according to history of psychiatric problems, if replicated, might be helpful in screening strategies.

  • 29.
    Dahlbom, Josefin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Lagman, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Lundstedt-Enkel, Katrin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Sundström, Fredrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal Ecology.
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Boldness predicts social status in zebrafish (Danio rerio)2011In: PLoS ONE, ISSN 1932-6203, Vol. 6, no 8, e23565Article in journal (Refereed)
    Abstract [en]

    This study explored if boldness could be used to predict social status. First, boldness was assessed by monitoring individual zebrafish behaviour in (1) an unfamiliar barren environment with no shelter (open field), (2) the same environment when a roof was introduced as a shelter, and (3) when the roof was removed and an unfamiliar object (Lego® brick) was introduced. Next, after a resting period of minimum one week, social status of the fish was determined in a dyadic contest and dominant/subordinate individuals were determined as the winner/loser of two consecutive contests. Multivariate data analyses showed that males were bolder than females and that the behaviours expressed by the fish during the boldness tests could be used to predict which fish would later become dominant and subordinate in the ensuing dyadic contest. We conclude that bold behaviour is positively correlated to dominance in zebrafish and that boldness is not solely a consequence of social dominance.

  • 30. Dahlgren, Angelica
    et al.
    Wargelius, Hanna-Linn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Berglund, Kristina J.
    Fahlke, Claudia
    Blennow, Kaj
    Zetterberg, Henrik
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Berggren, Ulf
    Balldin, Jan
    Do Alcohol-dependent Individuals with DRD2 A1 Allele Have an Increased Risk of Relapse?: A Pilot Study2011In: Alcohol and Alcoholism, ISSN 0735-0414, E-ISSN 1464-3502, Vol. 46, no 5, 509-513 p.Article in journal (Refereed)
    Abstract [en]

    Aims: The TaqIA polymorphism of the dopamine D2 receptor (DRD2) gene has been extensively studied in relation to alcoholism, and the TaqI A1 allele appears to be over-represented in alcohol-dependent individuals. In a recent study, this allele has also been associated with a highly increased mortality rate in alcohol-dependent individuals. In the present study, we investigated whether the TaqI A1 allele of the DRD2 gene region was associated with a higher relapse rate in alcohol-dependent individuals. Methods: Adult women (n = 10) and men (n = 40) with a diagnosis of alcohol-dependence were recruited from two Swedish 12-step treatment units for alcoholism. Subjects were genotyped for the TaqIA polymorphism. On average, 11/2 year after the end of the treatment program, subjects were re-interviewed by using the alcohol-related items from the Addiction Severity Index follow-up version. Results: Thirty-three (66%) subjects self-reported relapse and 17 (34%) abstinence during the follow-up period. Thirty-sex percent (18/50) were carriers of the A1 allele of the DRD2 gene region, and 64% (32/50) were non-carriers. Among the carriers of the A1 allele, 89% (16/18) reported relapse in contrast to 53% (17/32) in the non-carriers (P = 0.01; odds ratio = 7.1). Conclusion: The present study is, to our knowledge, the first report of an association between the TaqI A1 allele and a substantially increased relapse rate. It should be emphasized that the number of subjects is relatively small, and this investigation should therefore be considered as a pilot study.

  • 31.
    Damberg, Mattias
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Transcription Factor AP-2 in Relation to Serotonergic Functions in the Central Nervous System2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Eukaryotic gene transcription plays a regulatory role in mammalian developmental processes. It has been shown that transcriptional control is an important mechanism for specification of neurotransmitter phenotypes. In the mammalian central nervous system, the transcription factor AP-2 family is one of the critical regulatory factors for neural gene expression and neuronal development. It has been shown that several genes in the monoaminergic systems have AP-2 binding sites in regulatory regions, suggesting a regulatory role of AP-2 also in the adult brain. Brainstem monoamines are implicated in the expression of personality traits and imbalances in these systems may give rise to psychiatric disorders.

    The gene encoding AP-2β includes a polymorphic region consisting of a tetranucleotide repeat of [CAAA]4-5 in intron 2. Studies on AP-2β genotype in relation to personality and platelet MAO activity, a trait-dependant marker for personality, are presented in this thesis. Furthermore, correlations between brainstem levels of AP-2α and AP-2β and monoamine turnover in projection areas in rat forebrain are reported. These results strengthen the notion that the AP-2 family is important regulators of the monoaminergic systems in the adult brain. Furthermore, two studies are presented in this thesis with analyses indicating a role for AP-2 in the molecular mechanism of antidepressant drugs.

    Altogether, this thesis presents data supporting our notion that the transcription factor AP-2 family is involved in the regulation of the monoaminergic systems both pre- and postnatally, and, therefore, might be involved in the pathophysiology of neuropsychiatric disorders.

  • 32. Do Rego, Jean-Luc
    et al.
    Seong, Jae Young
    Burel, Delphine
    Luu-The, Van
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Tsutsui, Kazuyoshi
    Pelletier, Georges
    Tonon, Marie-Christine
    Vaudry, Hubert
    Steroid biosynthesis within the frog brain: a model of neuroendocrine regulation2009In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1163, 83-92 p.Article in journal (Refereed)
    Abstract [en]

    There is now clear evidence that the brain, similar to the adrenal gland, gonads, and placenta, is a steroidogenic organ. Notably in the frog brain, the presence of various steroidogenic enzymes has been detected by immunohistochemistry in specific populations of neurons and/or glial cells. These steroidogenic enzymes are biologically active, as shown by the ability of brain tissue explants to convert [(3)H]pregnenolone into various radiolabeled steroids. The frog brain has also been extensively used as a model to study the mechanism of regulation of neurosteroidogenesis by neurotransmitters and neuropeptides. It has been demonstrated that the biosynthesis of neurosteroids is inhibited by gamma-aminobutyric acid (GABA), acting through GABA(A) receptors, and neuropeptide Y, acting through Y1 receptors, and is stimulated by the octadecaneuropeptide (ODN), acting through central-type benzodiazepine receptors, triakontatetraneuropeptide (TTN), acting through peripheral-type benzodiazepine receptors, and vasotocin, acting through V1a-like receptors. These data indicate that some of the neurophysiological effects of neurotransmitters and neuropeptides may be mediated through modulation of neurosteroid biosynthesis.

  • 33.
    Ekmark-Lewén, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Flygt, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Kiwanuka, Olivia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Meyerson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Lewén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Traumatic axonal injury in the mouse is accompanied by a dynamic inflammatory response, astroglial reactivity and complex behavioral changes2013In: Journal of Neuroinflammation, ISSN 1742-2094, Vol. 10, no 1, 44- p.Article in journal (Refereed)
    Abstract [en]

    Background

    Diffuse traumatic axonal injury (TAI), a common consequence of traumatic brain injury, is associated with high morbidity and mortality. Inflammatory processes may play an important role in the pathophysiology of TAI. In the murine central fluid percussion injury (cFPI) TAI model, the neuroinflammatory and astroglial response and behavioral changes are unknown.

    Methods

    Twenty cFPI-injured and nine sham-injured mice were used, and the neuroinflammatory and astroglial response was evaluated by immunohistochemistry at 1, 3 and 7 days post-injury. The multivariate concentric square field test (MCSF) was used to compare complex behavioral changes in mice subjected to cFPI (n = 16) or sham injury (n = 10). Data was analyzed using non-parametric statistics and principal component analysis (MCSF data).

    Results

    At all post-injury time points, beta-amyloid precursor protein (beta-APP) immunoreactivity revealed widespread bilateral axonal injury and IgG immunostaining showed increased blood--brain barrier permeability. Using vimentin and glial fibrillary acidic protein (GFAP) immunohistochemistry, glial cell reactivity was observed in cortical regions and important white matter tracts peaking at three days post-injury. Only vimentin was increased post-injury in the internal capsule and only GFAP in the thalamus. Compared to sham-injured controls, an increased number of activated microglia (MAC-2), infiltrating neutrophils (GR-1) and T-cells (CD3) appearing one day after TAI (P<0.05 for all cell types) was observed in subcortical white matter. In the MCSF, the behavioral patterns including general activity and exploratory behavior differed between cFPI mice and sham-injured controls.

    Conclusions

    Traumatic axonal injury in mice resulted in marked bilateral astroglial and neuroinflammatory responses and complex behavioral changes. The cFPI model in mice appears suitable for the study of injury mechanisms, including neuroinflammation, and the development of treatments targeting traumatic axonal injury.

  • 34.
    Ekmark-Lewén, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Lewén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Meyerson, Bengt J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    The Multivariate Concentric Square Field Test Reveals Behavioral Profiles of Risk Taking, Exploration, and Cognitive Impairment in Mice Subjected to Traumatic Brain Injury2010In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 27, no 9, 1643-1655 p.Article in journal (Refereed)
    Abstract [en]

    There is a need for more efficient tests to evaluate functional outcome following experimental traumatic brain injury (TBI), reflecting deficits in cognitive, sensory, and motor functions that are seen in TBI patients. The Multivariate Concentric Square Field (TM) (MCSF) test is a relatively new behavioral model that measures exploration, risk taking, risk assessment, and shelter seeking, all of which are evolutionarily-conserved strategies for survival. The multivariate design enables scoring of different functional domains in a single test situation, with a free choice of optional environmental settings. Furthermore, repeated trials permits cognitive effects to be measured. In the present study, 11 anesthetized C57BL6 mice received controlled cortical injury (CCI) (0.5mm and 3.3 m/sec) over the right parietal cerebral cortex or sham surgery (n - 12). Naive mice (n 12) not subjected to any surgical procedure were also included. The animals were evaluated in the MCSF test at 2 and 7 days post-surgery, and behavioral profiles were analyzed. The results revealed differences in risk taking and explorative behavior between the sham animals and the animals subjected to trauma. Animals subjected to trauma were characterized by taking more risks and had a higher level of exploration activity, but they sought less shelter. Repeated exposure to the MCSF caused a general decrease in activity in the naive and sham group, while a more specific behavioral impairment was seen in injured mice, suggesting cognitive dysfunction. We submit that the MCSF test is a useful complementary tool for functional outcome evaluation in experimental TBI.

  • 35.
    Fredriksson, Robert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Gloriam, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Höglund, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Lagerström, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Schiöth, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    There exist at least 30 human G-protein-coupled receptors with long Ser/Thr-rich N-termini2003In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 301, no 3, 752-734 p.Article in journal (Refereed)
    Abstract [en]

    We report six novel members of the superfamily of human G-protein coupled receptors (GPCRs) found by searches in the human genome databases, termed GPR123, GPR124, GPR125, GPR126, GPR127, and GPR128. Phylogenetic analysis demonstrates that these are additional members of the family of GPCRs with long N-termini, previously termed EGF-7TM, LNB-7TM, B2 or LN-7TM, showing that there exist at least 30 such GPCRs in the human genome. Three of these receptors form their own phylogenetic cluster, while two other places in a cluster with the previously reported HE6 and GPR56 (TM7XN1) and one with EMR1-3. All the novel receptors have a GPS domain in their N-terminus, except GPR123, as well as long Ser/Thr rich regions forming mucin-like stalks. GPR124 and GPR125 have a leucine rich repeat (LRR), an immunoglobulin (Ig) domain, and a hormone-binding domain (HBD). The Ig domain shows similarities to motilin and titin, while the LRR domain shows similarities to LRIG1 and SLIT1-2. GPR127 has one EGF domain while GPR126 and GPR128 do not contain domains that are readily recognized in other proteins beyond the GPS domain. We found several human EST sequences for most of the receptors showing differential expression patterns, which may indicate that some of these receptors participate in central functions while others are more likely to have a role in the immune or reproductive systems.

  • 36. Fredriksson, Robert
    et al.
    Höglund, Pär
    Gloriam, David
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Lagerström, Malin
    Schiöth, Helgi
    Seven evolutionarily conserved human rhodopsin G protein-coupled receptors lacking close relatives.2003In: FEBS Letters, ISSN 0014-5793, Vol. 554, no 3, 381-388 p.Article in journal (Refereed)
  • 37. Furmark, Tomas
    et al.
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Henningsson, Susanne
    Ahs, Fredrik
    Faria, Vanda
    Linnman, Clas
    Pissiota, Anna
    Frans, Orjan
    Bani, Massimo
    Bettica, Paolo
    Pich, Emilio Merlo
    Jacobsson, Eva
    Wahlstedt, Kurt
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Långström, Bengt
    Eriksson, Elias
    Fredrikson, Mats
    A link between serotonin-related gene polymorphisms, amygdala activity, and placebo-induced relief from social anxiety2008In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 28, no 49, 13066-74 p.Article in journal (Refereed)
    Abstract [en]

    Placebo may yield beneficial effects that are indistinguishable from those of active medication, but the factors underlying proneness to respond to placebo are widely unknown. Here, we used functional neuroimaging to examine neural correlates of anxiety reduction resulting from sustained placebo treatment under randomized double-blind conditions, in patients with social anxiety disorder. Brain activity was assessed during a stressful public speaking task by means of positron emission tomography before and after an 8 week treatment period. Patients were genotyped with respect to the serotonin transporter-linked polymorphic region (5-HTTLPR) and the G-703T polymorphism in the tryptophan hydroxylase-2 (TPH2) gene promoter. Results showed that placebo response was accompanied by reduced stress-related activity in the amygdala, a brain region crucial for emotional processing. However, attenuated amygdala activity was demonstrable only in subjects who were homozygous for the long allele of the 5-HTTLPR or the G variant of the TPH2 G-703T polymorphism, and not in carriers of short or T alleles. Moreover, the TPH2 polymorphism was a significant predictor of clinical placebo response, homozygosity for the G allele being associated with greater improvement in anxiety symptoms. Path analysis supported that the genetic effect on symptomatic improvement with placebo is mediated by its effect on amygdala activity. Hence, our study shows, for the first time, evidence of a link between genetically controlled serotonergic modulation of amygdala activity and placebo-induced anxiety relief.

  • 38.
    Fällmar, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Studies of the Neuropeptide Y Receptor Y2 in Human and Zebrafish2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The G-protein coupled receptors (GPCRs) comprise the largest family of receptors in humans and other vertebrates. They are embedded in the cell membrane and are activated by many different signaling molecules. Activation modulates cellular signal transduction pathways and influences many physiological processes. Therefore the GPCRs are important as targets for numerous drugs.

    The receptors for NPY (neuropeptide Y) belong to GPCRs of Class A (rhodopsin-like). NPY and its related peptides PYY and PP are involved in the regulation of appetite, blood pressure and many other processes. They share a common structure and interact with the receptors Y1, Y2, Y4 and Y5 in mammals, and, in addition, Y7 and Y8 in amphibians and bony fishes.

    This thesis is focused on the human Y2 receptor, known to reduce appetite, by investigating the importance of thirteen amino acid residues for ligand binding. Mutagenesis followed by functional expression and receptor binding was conducted. During the course of this work several new GPCR crystal structures have been resolved, thereby improving the receptor modeling in papers I-III. The major finding is that even though the Y1 and Y2 receptors have evolved from a common ancestor, their points of ligand interaction differ and have thus changed during evolution. In general, the positions investigated resulted in milder changes in the ligands’ affinities for Y2 compared to Y1. These findings were incorporated in the design of new Y1 and Y2 receptor models, leading to improved understanding of how such divergent receptors, sharing only 30 percent sequence identity, can still interact with the same ligands. Notably, several of the mutations introduced in Y2 resulted in increased affinity.

    A novel NPY receptor gene named Y2-2 was identified in the genomes of zebrafish and medaka. This brings the number of zebrafish NPY receptors to seven. The binding characteristics of zebrafish Y2-2 differed from zebrafish Y2 mainly in the interaction with NPY13-36 and the antagonist BIIE0246.

    In conclusion, these results increase our understanding of ligand interactions with GPCRs and will be useful for refinement of ligand-receptor models for future development of receptor subtype-selective drugs.

  • 39.
    Fällmar, Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Sundström, Görel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Lundell, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Mohell, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Neuropeptide Y/peptide YY receptor Y2 duplicate in zebrafish with unique introns displays distinct peptide binding properties2011In: Comparative Biochemistry and Physiology - Part B: Biochemistry & Molecular Biology, ISSN 1096-4959, E-ISSN 1879-1107, Vol. 160, no 4, 166-173 p.Article in journal (Other academic)
    Abstract [en]

    The neuropeptide Y-family peptides and receptors are involved in a broad range of functions including appetite regulation. Both the peptide genes and the receptor genes are known to have duplicated in early vertebrate evolution. The ancestral jawed vertebrate had 7 NPY receptors but the number varies between 4 and 7 in extant vertebrates. Herein we describe the identification of an additional NPY receptor in two fish species, zebrafish and medaka. They cluster together with the Y2 receptors in phylogenetic analyses and seem to be orthologous to each other that is why we have named them Y2-2. Their genes differ from Y2 in having introns in the coding region. Binding studies with zebrafish Y2-2 receptors show that the three endogenous peptides NPY, PYYa and PYYb have similar affinities, 0.15-0.66nM. This is in contrast to the Y2 receptor where they differed considerably from one another. N-terminally truncated NPY binds poorly and the Y2 antagonist BIIE0246 binds well to Y2-2, results that are reversed in comparison to Y2. Zebrafish Y2-2 mRNA was detected by PCR in the intestine and the eye, but not in the brain. In conclusion, we have found a novel Y2-like NPY/PYY receptor that probably arose in early teleost fish evolution.

  • 40.
    Fällmar, Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Åkerberg, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Gutiérrez-de-Terán, Hugo
    Lundell, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Mohell, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Identification of positions in the human neuropeptide Y/peptide YY receptor Y2 that contribute to pharmacological differences between receptor subtypes2011In: Neuropeptides, ISSN 0143-4179, E-ISSN 1532-2785, Vol. 45, no 4, 293-300 p.Article in journal (Refereed)
    Abstract [en]

    The members of the neuropeptide Y (NPY) family are key players in food-intake regulation. In humans this family consists of NPY, peptide YY (PYY) and pancreatic polypeptide (PP) which interact with distinct preference for the four receptors showing very low sequence identity, i.e. Y1, Y2, Y4 and Y5. The binding of similar peptides to these divergent receptors makes them highly interesting for mutagenesis studies. We present here a site-directed mutagenesis study of four amino acid positions in the human Y2 receptor. T(3.40) was selected based on sequence alignments both between subtypes and between species and G(2.68), L(4.60) and Q(6.55) also on previous binding studies of the corresponding positions in the Y1 receptor. The mutated receptors were characterized pharmacologically with the peptide agonists NPY, PYY, PYY(3-36), NPY(13-36) and the non-peptide antagonist BIIE0246. Interestingly, the affinity of NPY and PYY(3-36) increased for the mutants T(3.40)I and Q(6.55)A. Increased affinity was also observed for PYY to Q(6.55)A. PYY(3-36) displayed decreased affinity for G(2.68)N and L(4.60)A whereas binding of NPY(13-36) was unaffected by all mutations. The antagonist BIIE0246 showed decreased affinity for T(3.40)I, L(4.60)A and Q(6.55)A. Although all positions investigated were found important for interaction with at least one of the tested ligands the corresponding positions in hY1 seem to be of greater importance for ligand binding. Furthermore these data indicate that binding of the agonists and the antagonist differs in their points of interaction. The increase in the binding affinity observed may reflect an indirect effect caused by a conformational change of the receptor. These findings will help to improve the structural models of the human NPY receptors.

  • 41.
    Gingnell, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Comasco, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Sundström-Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Neuroticism-related personality traits are related to symptom severity in patients with premenstrual dysphoric disorder and to the serotonin transporter gene-linked polymorphism 5-HTTPLPR2010In: Archives of Women's Mental Health, ISSN 1434-1816, E-ISSN 1435-1102, Vol. 13, no 5, 417-423 p.Article in journal (Refereed)
    Abstract [en]

    Neuroticism has been linked to a functional polymorphism in the serotonin transporter gene (5-HTTLPR), with short-allele carriers being overrepresented among high-scorers on neuroticism. Studies evaluating neuroticism-related personality traits in relation to the 5-HTTLPR polymorphism among patients with premenstrual dysphoric disorder (PMDD) and are lacking. The primary aim of this study was to evaluate the relationship between PMDD and neuroticism-related personality traits, and secondly, to relate the personality trait scores of PMDD patients to experienced symptom severity and to the 5-HTTLPR short allele. Thirty PMDD patients and 55 asymptomatic healthy controls were included in the study. The Swedish Universities Scale of Personality was used to evaluate personality traits. Genotype analyses were available in 27 PMDD patients and 18 healthy controls. Women with PMDD displayed higher levels of neuroticism-related personality traits (psychic trait anxiety, somatic trait anxiety, embitterment, stress susceptibility and mistrust) than healthy controls, and these effects were most prominent in women with more severe luteal phase symptoms. Furthermore, PMDD patients with at least one copy of the short allele of the 5-HTTLPR polymorphism scored higher on psychic trait anxiety and lack of assertiveness than PMDD patients who were homozygous for the long allele. PMDD patients who suffer from more severe luteal phase symptoms also display increased scores of neuroticism-related personality traits in comparison with healthy controls. Within the group of PMDD patients, differences in certain personality trait scores are associated with the short allele of the 5-HTTLPR polymorphism.

  • 42.
    Gloriam, David
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Bjarnadóttir, Thóra
    Yan, Yi-Lin
    Postlethwait, John
    Schiöth, Helgi
    Fredriksson, Robert
    The repertoire of trace amine G-protein-coupled receptors: large expansion in zebrafish2005In: Molecular Phylogenetics and Evolution, ISSN 1055-7903, Vol. 35, no 2, 470-482 p.Article in journal (Refereed)
  • 43.
    Gloriam, David E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    G Protein-Coupled Receptors; Discovery of New Human Members and Analyses of the Entire Repertoires in Human, Mouse and Rat2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    G protein-coupled receptors (GPCRs) are signal mediators that have a prominent role in the regulation of physiological processes and they make up the targets for 30-45% of all drugs.

    Papers I and II describe the discovery of new human GPCRs belonging to the Rhodopsin family, a family which contains many common drug targets. The new receptors have only weak relationships to previously known GPCRs. However, they have been evolutionary conserved in several species and most of them display distinct expression patterns.

    In paper III we identified new human GPCRs belonging to the Adhesion family, which is characterised by very long N-termini containing conserved domains. The different compositions of conserved domains as well as the expression patterns suggest that the Adhesions can have several different functions.

    In paper IV we revealed remarkable species variations in the repertoires of Trace Amine-Associated Receptors (TAARs), which are relatives of the biogenic amine receptors. The human, mouse and rat TAAR genes are located in only one locus and are therefore most likely the result of gene tandem duplications. 47 of the 57 zebrafish TAARs were mapped to nine different loci on six chromosomes containing from 1 to 27 genes each. This study suggests that the TAARs arose through several different mechanisms involving tetraploidisation, block duplications, and local duplication events.

    Papers V and VI are overall analyses of the repertoires of GPCRs in humans, mice and rats; which contain approximately 800, 1800 and 1900 members, respectively. The repertoires were compared to distinguish between species-specific and common (orthologous) members, something which is important for example when predicting drug effects from experiments in rodents. The Glutamate, Adhesion, Frizzled and Secretin families show no or very little variation between human and rodents, whereas the repertoires of olfactory, vomeronasal and Taste2 receptors display large differences between all three species.

  • 44.
    Gloriam, David
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Fredriksson, Robert
    Schiöth, Helgi
    The overall repertoire of G protein-coupled receptor in ratsManuscript (Other academic)
  • 45.
    Gloriam, David
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Schiöth, Helgi
    Fredriksson, Robert
    Nine new human Rhodopsin family G-protein coupled receptors: identification, sequence characterisation and evolutionary relationship.2005In: Biochimica et Biophysica Acta (BBA) - General Subjects, ISSN 0304-4165, Vol. 1722, no 3, 235-246 p.Article in journal (Refereed)
  • 46.
    Gokturk, Camilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Schultze, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Nilsson, Kent W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    von Knorring, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Hallman, Jarmila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Serotonin transporter (5-HTTLPR) and monoamine oxidase (MAOA) promoter polymorphisms in women with severe alcoholism2008In: Archives of Women's Mental Health, ISSN 1434-1816, E-ISSN 1435-1102, Vol. 11, no 5-6, 347-355 p.Article in journal (Refereed)
    Abstract [en]

    The serotonin system is known to play a pivotal role for mood, behaviour and psychic illness as e.g. alcoholism. Alcoholism in both males and females has been associated with polymorphisms in genes encoding for proteins of importance for central serotonergic function. Genotyping of two functional polymorphisms in the promoter region of the serotonin transporter and monoamine oxidase-A, respectively, (5-HTT-LPR and MAOA-VNTR), was performed in a group of women with severe alcohol addiction. A large sample of adolescent females from a normal population was used as controls. A significantly higher frequency of the LL 5-HTT genotype (high activity) was found in female addicts without a known co-morbid psychiatric disorder than in the controls. Genotype of the MAOA-VNTR polymorphism did not differ significantly between addicts and controls. However, within the group of alcoholics, when the patients with known co-morbid psychiatric disorders were excluded, aggressive anti-social behaviour was significantly linked to the presence of the high activity MAOA allele. The pattern of associations between genotypes of 5-HTT-LPR and MAOA-VNTR in women with severe alcoholism differs from most corresponding studies on males.

  • 47.
    Gokturk, Camilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Sugimoto, Haruyo
    Blomgren, Bo
    Roomans, Godfried M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Sjöquist, Mats
    Macrovascular changes in mice overexpressing human semicarbazide-sensitive amine oxidase in smooth muscle cells2007In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1879-1905, Vol. 20, no 7, 743-750 p.Article in journal (Refereed)
    Abstract [en]

    Background: The catalytic activity of semicarbazide-sensitive amine oxidase (SSAO) is increased in diabetes, as well as in other disorders of cardiovascular origin. Our hypothesis is that SSAO is involved in the synthesis or maturation of elastin in vascular tissue. An increased SSAO activity can thereby be involved in the development of vascular damage. Methods: Elastin quantification was performed in aorta of transgenic mice overexpressing the human form of SSAO, using electron microscopy. Furthermore, lung capacity was measured using a spirometry-mimicking method, developed for mice. The effect of vasoactive substances was estimated by measuring mean arterial pressure and pulse pressure under anesthesia. Results: No differences in elastin quantity or lung capacity could be observed between transgenic or nontransgenic littermates. Pulse pressure was higher in transgenic mice, and electron microscopy of aorta showed elastin fibers parallel with the aorta wall (ie, straight fibers instead of folded compared with control mice). No difference in the response to adrenaline or sodium chloride was observed between the transgenic and control mice. The control mice had a clear decrease in blood pressure (BP) with a longer duration as a response to injection of a nitric oxide (NO) donor, sodium nitroprusside, compared with transgenic mice where only a minor response was observed. The SSAO activity in serum of control mice was elevated in response to injection of the NO donor, but not in response to a ganglion blocker. Conclusions: An elevated pulse pressure, together with an abnormal elastin structure in the aorta, suggests a rigidity of large arteries as a result of an elevated SSAO activity as well as a physiologic role for SSAO in elastin maturation.

  • 48.
    Granas, Charlotta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Nordvall, G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Mutagenesis of the human 5-HT1B receptor: Differences from the closely related 5-HT1A receptor and the role of residue F331 in signal transduction1998In: Journal of Receptor and Signal Transduction Research, ISSN 1079-9893, E-ISSN 1532-4281, Vol. 18, no 4-6, 225-241 p.225-241 p.Article in journal (Refereed)
    Abstract [en]

    We have used a combination of sequence comparisons, computer-based modeling and site-directed mutagenesis to investigate the molecular interactions involved in ligand binding and signal transduction of the human 5-HT1B receptor. Two amino acid residues, S212 in transmembrane region (TM) V and F331 in TM VI, were replaced by alanines. These amino acids are conserved in many G protein-coupled receptors and therefore likely to be important for receptor function. The mutant receptors were expressed in Chinese hamster ovary cells. The 5-HT-like agonist 5-carboxamidotryptamine (5-CT) bound with 15-fold lower affinity to the S212A mutant as compared to wild-type receptor and the antagonist methiothepin bound with 17-fold lower affinity to the F331A mutant. No reduction in the affinity of 5-HT was seen for the S212A mutant, although an equivalent mutation in the 5-HT1A receptor resulted in a 100-fold reduction of 5-HT binding. The inhibition of forskolin-stimulated cyclic AMP production by 5-HT was significantly reduced in cells expressing the F331A mutant, even though the endogenous ligand 5-HT bound with somewhat increased affinity. Methiothepin acted as an inverse agonist and increased the forskolin-stimulated cyclic AMP production at both the wild-type receptor and the mutants, and the effect was stronger on the F331A mutant. These results suggest that F331 is involved in the conformational changes necessary for signal transduction.

  • 49. Haeffel, Gerald J.
    et al.
    Getchell, Marya
    Koposov, Roman A.
    Yrigollen, Carolyn M.
    DeYoung, Colin G.
    af Klinteberg, Britt
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Ruchkin, Vladislav V.
    Yale Child Study Center.
    Grigorenko, Elena L.
    Association between polymorphisms in the dopamine transporter gene and depression: evidence for a gene-environment interaction in a sample of juvenile detainees2008In: Psychological Science, ISSN 0956-7976, E-ISSN 1467-9280, Vol. 19, no 1, 62-69 p.Article in journal (Refereed)
    Abstract [en]

    Previous research has generated examples of how genetic and environmental factors can interact to create risk for psychopathology. Using a gene-by-environment (G x E) interaction design, we tested whether three polymorphisms in the dopamine transporter gene (DAT1, also referred to as SLC6A3, located at 5p15.33) interacted with maternal parenting style to predict first-onset episodes of depression. Participants were male adolescents (N= 176) recruited from a juvenile detention center in northern Russia. As hypothesized, one of the polymorphisms (rs40184) moderated the effect of perceived maternal rejection on the onset of major depressive disorder, as well as on suicidal ideation. Further, this G x E interaction was specific to depression; it did not predict clinically significant anxiety. These results highlight the need for further research investigating the moderating effects of dopaminergic genes on depression.

  • 50.
    Haitina, Tatjana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Ringholm, Aneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Kelly, Joanne
    Mundy, Nicholas I
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    High diversity in functional properties of melanocortin 1 receptor (MC1R) in divergent primate species is more strongly associated with phylogeny than coat color2007In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 24, no 9, 2001-2008 p.Article in journal (Refereed)
    Abstract [en]

    We have characterized the biochemical function of the melanocortin1 receptor (MC1R), a critical regulator of melanin synthesis,from 9 phylogenetically diverse primate species with varyingcoat colors. There is substantial diversity in melanocyte-stimulatinghormone (MSH) binding affinity and basal levels of activityin the cloned MC1Rs. MSH binding was lost independently in lemurand New World monkey lineages, whereas high basal levels ofMC1R activity occur in lemurs and some New World monkeys andOld World monkeys. Highest levels of basal activity were foundin the MC1R of ruffed lemurs, which have the E94K mutation thatleads to constitutive activation in other species. In 3 species(2 lemurs and the howler monkey), we report the novel findingthat binding and inhibition of MC1R by agouti signaling protein(ASIP) can occur when MSH binding has been lost, thus enablingcontinuing regulation of the melanin type via ASIP expression.Together, these findings can explain the previous paradox ofa predominantly pheomelanic coat in the red ruffed lemur (Vareciarubra). The presence of a functional, MSH-responsive MC1R inorangutan demonstrates that the mechanism of red hair generationin this ape is different from the prevalent mechanism in Europeanhuman populations. Overall, we have found unexpected diversityin MC1R function among primates and show that the evolutionof the regulatory control of MC1R activity occurs by independentvariation of 3 distinct mechanisms: basal MC1R activity, MSHbinding and activation, and ASIP binding and inhibition. Thisdiversity of function is broadly associated with primate phylogenyand does not have a simple relation to coat color phenotypewithin primate clades.

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