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  • 51.
    Lukoyanov, Nikolay
    et al.
    Univ Porto, Fac Med, Dept Biomed, Porto, Portugal.
    Carvalho, Liliana
    Univ Porto, Fac Med, Inst Invest & Inovacao Saude, Inst Biol Mol & Celular,Dept Biomed, Porto, Portugal.
    Watanabe, Hiroyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Zhang, Mengliang
    Lund Univ, Dept Expt Med Sci, Neuronano Res Ctr, Lund, Sweden.
    Sarkisyan, Daniil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kononenko, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bazov, Igor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Iakovleva, Tatiana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schouenborg, Jens
    Lund Univ, Dept Expt Med Sci, Neuronano Res Ctr, Lund, Sweden.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Contralesional Hindlimb Motor Response Induced By Unilateral Brain Injury: Evidence For Extra Spinal Mechanism2018In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 35, no 16, p. A201-A201Article in journal (Other academic)
  • 52. Maximyuk, O.
    et al.
    Khmyz, V.
    Lindskog, C-J
    Vukojevic, V.
    Ivanova, T.
    Bazov, Igor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hauser, K. F.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Krishtal, O.
    Plasma membrane poration by opioid neuropeptides: a possible mechanism of pathological signal transduction2015In: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 6, article id e1683Article in journal (Refereed)
    Abstract [en]

    Neuropeptides induce signal transduction across the plasma membrane by acting through cell-surface receptors. The dynorphins, endogenous ligands for opioid receptors, are an exception; they also produce non-receptor-mediated effects causing pain and neurodegeneration. To understand non-receptor mechanism(s), we examined interactions of dynorphins with plasma membrane. Using fluorescence correlation spectroscopy and patch-clamp electrophysiology, we demonstrate that dynorphins accumulate in the membrane and induce a continuum of transient increases in ionic conductance. This phenomenon is consistent with stochastic formation of giant (similar to 2.7 nm estimated diameter) unstructured non-ion-selective membrane pores. The potency of dynorphins to porate the plasma membrane correlates with their pathogenic effects in cellular and animal models. Membrane poration by dynorphins may represent a mechanism of pathological signal transduction. Persistent neuronal excitation by this mechanism may lead to profound neuropathological alterations, including neurodegeneration and cell death.

  • 53. Meng, Weida
    et al.
    Sjöholm, Louise K
    Kononenko, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Tay, Nicole
    Zhang, Dandan
    Sarkisyan, Daniil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Geske, Jennifer R
    Ing, Alex
    Qiu, Wenqing
    Watanabe, Hiroyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Almamoun, Radwa
    Frieling, Helge
    Bleich, Stefan
    Cui, Donghong
    Biernacka, Joanna M
    Mayfield, R Dayne
    Dang, Yongjun
    Karpyak, Victor M
    Schumann, Gunter
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ekström, Tomas J
    Rüegg, Joelle
    Liu, Yun
    Genotype-dependent epigenetic regulation of DLGAP2 in alcohol use and dependence.2019In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578Article in journal (Refereed)
    Abstract [en]

    Alcohol misuse is a major public health problem originating from genetic and environmental risk factors. Alterations in the brain epigenome may orchestrate changes in gene expression that lead to alcohol misuse and dependence. Through epigenome-wide association analysis of DNA methylation from human brain tissues, we identified a differentially methylated region, DMR-DLGAP2, associated with alcohol dependence. Methylation within DMR-DLGAP2 was found to be genotype-dependent, allele-specific and associated with reward processing in brain. Methylation at the DMR-DLGAP2 regulated expression of DLGAP2 in vitro, and Dlgap2-deficient mice showed reduced alcohol consumption compared with wild-type controls. These results suggest that DLGAP2 may be an interface for genetic and epigenetic factors controlling alcohol use and dependence.

  • 54.
    Mueller, Christian P.
    et al.
    Friedrich Alexander Univ Erlangen Nuremberg, Univ Clin, Dept Psychiat & Psychotherapy, Sect Addict Med, Schwabachanlage 6, D-91054 Erlangen, Germany.
    Chu, Congying
    Kings Coll London, Inst Psychiat Psychol & Neurosci, Ctr Populat Neurosci & Stratified Med PONS, De Crespigny Pk, London SE5 8AF, England;Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC SGDP Ctr, De Crespigny Pk, London SE5 8AF, England.
    Qin, Liya
    Univ N Carolina, Sch Med, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USA.
    Liu, Chunyu
    Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA;NHLBI, Populat Sci Branch, Div Intramural Res, Bethesda, MD 20824 USA;Boston Univ, Sch Publ Hlth, 715 Albany St, Boston, MA 02118 USA.
    Xu, Bing
    Kings Coll London, Inst Psychiat Psychol & Neurosci, Ctr Populat Neurosci & Stratified Med PONS, De Crespigny Pk, London SE5 8AF, England;Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC SGDP Ctr, De Crespigny Pk, London SE5 8AF, England.
    Gao, He
    Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, London W2 1PG, England.
    Ruggeri, Barbara
    Kings Coll London, Inst Psychiat Psychol & Neurosci, Ctr Populat Neurosci & Stratified Med PONS, De Crespigny Pk, London SE5 8AF, England;Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC SGDP Ctr, De Crespigny Pk, London SE5 8AF, England.
    Hieber, Saskia
    Friedrich Alexander Univ Erlangen Nuremberg, Univ Clin, Dept Psychiat & Psychotherapy, Sect Addict Med, Schwabachanlage 6, D-91054 Erlangen, Germany.
    Schneider, Julia
    Friedrich Alexander Univ Erlangen Nuremberg, Inst Biochem & Mol Med, Fahrstr 17, D-91054 Erlangen, Germany.
    Jia, Tianye
    Kings Coll London, Inst Psychiat Psychol & Neurosci, Ctr Populat Neurosci & Stratified Med PONS, De Crespigny Pk, London SE5 8AF, England;Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC SGDP Ctr, De Crespigny Pk, London SE5 8AF, England.
    Tay, Nicole
    Kings Coll London, Inst Psychiat Psychol & Neurosci, Ctr Populat Neurosci & Stratified Med PONS, De Crespigny Pk, London SE5 8AF, England;Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC SGDP Ctr, De Crespigny Pk, London SE5 8AF, England.
    Akira, Shizuo
    Osaka Univ, Microbial Dis Res Inst, World Premier Int Immunol Frontiern Res Ctr, Lab Host Def, 1-1 Yamadaoka, Suita, Osaka 5650871, Japan.
    Satoh, Takashi
    Osaka Univ, Microbial Dis Res Inst, World Premier Int Immunol Frontiern Res Ctr, Lab Host Def, 1-1 Yamadaoka, Suita, Osaka 5650871, Japan.
    Banaschewski, Tobias
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Child & Adolescent Psychiat & Psychotherapy, J5, D-68159 Mannheim, Germany.
    Bokde, Arun L. W.
    Trinity Coll Dublin, Sch Med, Discipline Psychiat, Jamess St, Dublin 8, Ireland;Trinity Coll Dublin, Trin Coll Inst Neurosci, Jamess St, Dublin 8, Ireland.
    Bromberg, Uli
    Univ Med Ctr Hamburg Eppendorf, House W34,3 OG,Martinistr 52, D-20246 Hamburg, Germany.
    Buechel, Christian
    Univ Med Ctr Hamburg Eppendorf, House W34,3 OG,Martinistr 52, D-20246 Hamburg, Germany.
    Quinlan, Erin Burke
    Kings Coll London, Inst Psychiat Psychol & Neurosci, Ctr Populat Neurosci & Stratified Med PONS, De Crespigny Pk, London SE5 8AF, England;Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC SGDP Ctr, De Crespigny Pk, London SE5 8AF, England.
    Flor, Herta
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Cognit & Clin Neurosci, J5, D-68159 Mannheim, Germany;Univ Mannheim, Sch Social Sci, Dept Psychol, D-68131 Mannheim, Germany.
    Frouin, Vincent
    Univ Paris Saclay, CEA, NeuroSpin, F-91191 Gif Sur Yvette, France.
    Garavan, Hugh
    Univ Vermont, Dept Psychiat, Burlington, VT 05405 USA;Univ Vermont, Dept Psychol, Burlington, VT 05405 USA.
    Gowland, Penny
    Univ Nottingham, Sch Phys & Astron, Sir Peter Mansfield Imaging Ctr, Univ Pk, Nottingham NG7 2QX, England.
    Heinz, Andreas
    Charite Univ Med Berlin, Campus Charite Mitte, Dept Psychiat & Psychotherapy, Charitepl 1, D-10117 Berlin, Germany.
    Ittermann, Bernd
    PTB, Braunschweig, Germany;PTB, Abbestr 2-12, D-10587 Berlin, Germany.
    Martinot, Jean-Luc
    Univ Paris Saclay, Univ Paris Sud, INSERM, Unit 1000,Neuroimaging & Psychiat,DIGITEO Labs, Rue Noetzlin, F-91190 Gif Sur Yvette, France.
    Martinot, Marie-Laure Paillere
    Univ Paris Saclay, Univ Paris Sud, INSERM, Unit 1000,Neuroimaging & Psychiat, Gif Sur Yvette, France;Hop La Pitie Salpetriere, AP HP, Dept Child & Adolescent Psychiat, 47-83 Blvd Hop, F-75013 Paris, France.
    Artiges, Eric
    Univ Paris Saclay, Univ Paris Sud, INSERM, Unit 1000,Neuroimaging & Psychiat,DIGITEO Labs, Rue Noetzlin, F-91190 Gif Sur Yvette, France;Orsay Hosp, Psychiat Dept 91G16, Orsay, France.
    Lemaitre, Herve
    Univ Paris Sud, Sch Med, INSERM, Unit 1000,Neuroimaging & Psychiat, Gif Sur Yvette, France.
    Nees, Frauke
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Child & Adolescent Psychiat & Psychotherapy, J5, D-68159 Mannheim, Germany;Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Cognit & Clin Neurosci, J5, D-68159 Mannheim, Germany.
    Orfanos, Dimitri Papadopoulos
    Univ Paris Saclay, CEA, NeuroSpin, F-91191 Gif Sur Yvette, France.
    Paus, Tomas
    Univ Toronto, Rotman Res Inst, 3560 Bathurst St, Toronto, ON M6A 2E1, Canada;Univ Toronto, Dept Psychol, 3560 Bathurst St, Toronto, ON M6A 2E1, Canada;Univ Toronto, Dept Psychiat, 3560 Bathurst St, Toronto, ON M6A 2E1, Canada.
    Poustka, Luise
    Univ Med Ctr Gottingen, Dept Child & Adolescent Psychiat & Psychotherapy, von Siebold Str 5, D-37075 Gottingen, Germany;Med Univ Vienna, Clin Child & Adolescent Psychiat, Wahringer Gurtel 18-20, A-1090 Vienna, Austria.
    Millenet, Sabina
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Child & Adolescent Psychiat & Psychotherapy, J5, D-68159 Mannheim, Germany.
    Froehner, Juliane H.
    Tech Univ Dresden, Dept Psychiat, Chemnitzer Str 46a, D-01187 Dresden, Germany;Tech Univ Dresden, Neuroimaging Ctr, Chemnitzer Str 46a, D-01187 Dresden, Germany.
    Smolka, Michael N.
    Tech Univ Dresden, Dept Psychiat, Chemnitzer Str 46a, D-01187 Dresden, Germany;Tech Univ Dresden, Neuroimaging Ctr, Chemnitzer Str 46a, D-01187 Dresden, Germany.
    Walter, Henrik
    Charite Univ Med Berlin, Campus Charite Mitte, Dept Psychiat & Psychotherapy, Charitepl 1, D-10117 Berlin, Germany.
    Whelan, Robert
    Aras Phiarsaigh Trinity Coll Dublin, Sch Psychol, Dublin 2, Ireland;Aras Phiarsaigh Trinity Coll Dublin, Global Brain Hlth Inst, Dublin 2, Ireland.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Liu, Yun
    Minist Educ, Key Lab Metab & Mol Med, Shanghai, Peoples R China;Fudan Univ, Shanghai Med Coll, Dept Biochem & Mol Biol, Shanghai, Peoples R China.
    Desrivieres, Sylvane
    Kings Coll London, Inst Psychiat Psychol & Neurosci, Ctr Populat Neurosci & Stratified Med PONS, De Crespigny Pk, London SE5 8AF, England;Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC SGDP Ctr, De Crespigny Pk, London SE5 8AF, England.
    Elliott, Paul
    Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, London W2 1PG, England.
    Eulenburg, Volker
    Friedrich Alexander Univ Erlangen Nuremberg, Inst Biochem & Mol Med, Fahrstr 17, D-91054 Erlangen, Germany;Univ Leipzig, Dept Anaesthesiol & Intens Care Med, Liebigstr 20, D-04103 Leipzig, Germany.
    Levy, Daniel
    Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA;NHLBI, Populat Sci Branch, Div Intramural Res, Bethesda, MD 20824 USA.
    Crews, Fulton
    Univ N Carolina, Sch Med, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USA.
    Schumann, Gunter
    Kings Coll London, Inst Psychiat Psychol & Neurosci, Ctr Populat Neurosci & Stratified Med PONS, De Crespigny Pk, London SE5 8AF, England;Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC SGDP Ctr, De Crespigny Pk, London SE5 8AF, England.
    The Cortical Neuroimmune Regulator TANK Affects Emotional Processing and Enhances Alcohol Drinking: A Translational Study2019In: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 29, no 4, p. 1736-1751Article in journal (Refereed)
    Abstract [en]

    Alcohol abuse is a major public health problem worldwide. Understanding the molecular mechanisms that control regular drinking may help to reduce hazards of alcohol consumption. While immunological mechanisms have been related to alcohol drinking, most studies reported changes in immune function that are secondary to alcohol use. In this report, we analyse how the gene "TRAF family member-associated NF-kappa B activator" (TANK) affects alcohol drinking behavior. Based on our recent discovery in a large GWAS dataset that suggested an association of TANK, SNP rs197273, with alcohol drinking, we report that SNP rs197273 in TANK is associated both with gene expression (P = 1.16 x 10(-19)) and regional methylation (P = 5.90 x 10(-25)). A tank knock out mouse model suggests a role of TANK in alcohol drinking, anxiety-related behavior, as well as alcohol exposure induced activation of insular cortex NF-kappa B. Functional and structural neuroimaging studies among up to 1896 adolescents reveal that TANK is involved in the control of brain activity in areas of aversive interoceptive processing, including the insular cortex, but not in areas related to reinforcement, reward processing or impulsiveness. Our findings suggest that the cortical neuroimmune regulator TANK is associated with enhanced aversive emotional processing that better protects from the establishment of alcohol drinking behavior.

  • 55.
    Ossipov, Michael H.
    et al.
    Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, Arizona 85724.
    Bazov, Igor
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm S-17176, Sweden.
    Gardell, Luis R.
    Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, Arizona 85724.
    Kowal, Justin
    Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, Arizona 85724.
    Yakovleva, Tatiana
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm S-17176, Sweden.
    Usynin, Ivan
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm S-17176, Sweden.
    Ekström, Tomas J.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm S-17176, Sweden.
    Porreca, Frank
    Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, Arizona 85724.
    Bakalkin, Georgy
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm S-17176, Sweden.
    Control of chronic pain by the ubiquitin-proteasome system in the spinal cord2007In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 27, no 31, p. 8226-37Article in journal (Refereed)
    Abstract [en]

    Chronic pain is maintained in part by long-lasting neuroplastic changes in synapses and several proteins critical for synaptic plasticity are degraded by the ubiquitin-proteasome system (UPS). Here, we show that proteasome inhibitors administered intrathecally or subcutaneously prevented the development and reversed nerve injury-induced pain behavior. They also blocked pathological pain induced by sustained administration of morphine or spinal injection of dynorphin A, an endogenous mediator of chronic pain. Proteasome inhibitors blocked mechanical allodynia and thermal hyperalgesia in all three pain models although they did not modify responses to mechanical stimuli, but partially inhibited responses to thermal stimuli in control rats. In the spinal cord, these compounds abolished the enhanced capsaicin-evoked calcitonin gene-related peptide (CGRP) release and dynorphin A upregulation, both elicited by nerve injury. Model experiments demonstrated that the inhibitors may act directly on dynorphin-producing cells, blocking dynorphin secretion. Thus, the effects of proteasome inhibitors on chronic pain were apparently mediated through several cellular mechanisms indispensable for chronic pain, including those of dynorphin A release and postsynaptic actions, and of CGRP secretion. Levels of several UPS proteins were reduced in animals with neuropathic pain, suggesting that UPS downregulation, like effects of proteasome inhibitors, counteracts the development of chronic pain. The inhibitors did not produce marked or disabling motor disturbances at doses that were used to modify chronic pain. These results suggest that the UPS is a critical intracellular regulator of pathological pain, and that UPS-mediated protein degradation is required for maintenance of chronic pain and nociceptive, but not non-nociceptive responses in normal animals.

  • 56. Preuss, U. W.
    et al.
    Winham, S. J.
    Biernacka, J. M.
    Cunningham, J. M.
    Walker, D. L.
    Lewis, K. A.
    Geske, J. R.
    Colby, C. L.
    Zill, P.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karpyak, V. M.
    Minor Allele Of Pdyn Rs2281285 Snp Is Positively Associated With Drinking To Overcome Mental Or Somatic Problems2013In: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 37, no Suppl.2, p. 66A-66AArticle in journal (Other academic)
  • 57. Preuss, Ulrich W.
    et al.
    Winham, Stacey J.
    Biernacka, Joanna M.
    Geske, Jennifer R.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Koller, Gabriele
    Zill, Peter
    Soyka, Michael
    Karpyak, Victor M.
    PDYN rs2281285 Variant Association with Drinking to Avoid Emotional or Somatic Discomfort2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 11, p. e78688-Article in journal (Refereed)
    Abstract [en]

    Introduction: One of the proposed psychobiological pathways of craving attributes the desire for drinking in the context of tension, discomfort or unpleasant emotions, to "negative'' (or "relief'') craving. The aim of this study was to replicate a previously reported association of the PDYN rs2281285 variant with negative craving using a different phenotyping approach. Methods: The TaqMan (R) Genotyping Assay was used to genotype the rs2281285 variant in 417 German alcohol-dependent subjects. The presence of negative/relief craving was assessed by asking if participants ever ingested alcohol to avoid unwanted emotional or somatic discomfort. Results: The minor allele of rs2281285 was associated with an increased risk of drinking to avoid/escape unwanted emotional or somatic events (OR = 2.29, 95% CI = 1.08-4.85, p = 0.0298). Discussion: Despite the use of a different phenotyping approach to the measurement of negative craving, our results confirm the association between negative craving and PDYN rs2281285. Genetic markers of negative craving may help to identify subgroups of alcohol-dependent individuals vulnerable to relapse in the context of negative emotions or somatic discomfort, leading to the development of specifically tailored treatment strategies.

  • 58. Ruggeri, Barbara
    et al.
    Macare, Christine
    Stopponi, Serena
    Jia, Tianye
    Carvalho, Fabiana M
    Robert, Gabriel
    Banaschewski, Tobias
    Bokde, Arun L W
    Bromberg, Uli
    Büchel, Christian
    Cattrell, Anna
    Conrod, Patricia J
    Desrivières, Sylvane
    Flor, Herta
    Frouin, Vincent
    Gallinat, Jürgen
    Garavan, Hugh
    Gowland, Penny
    Heinz, Andreas
    Ittermann, Bernd
    Martinot, Jean Luc
    Martinot, Marie-Laure Paillère
    Nees, Frauke
    Papadopoulos-Orfanos, Dimitri
    Paus, Tomáš
    Poustka, Luise
    Smolka, Michael N
    Vetter, Nora C
    Walter, Henrik
    Whelan, Robert
    Sommer, Wolfgang H
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ciccocioppo, Roberto
    Schumann, Gunter
    Methylation of OPRL1 mediates the effect of psychosocial stress on binge drinking in adolescents2018In: Journal of Child Psychology and Psychiatry and Allied Disciplines, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 9, no 6, p. 50-658Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Nociceptin is a key regulator linking environmental stress and alcohol drinking. In a genome-wide methylation analysis, we recently identified an association of a methylated region in the OPRL1 gene with alcohol-use disorders.

    METHODS: Here, we investigate the biological basis of this observation by analysing psychosocial stressors, methylation of the OPRL1 gene, brain response during reward anticipation and alcohol drinking in 660 fourteen-year-old adolescents of the IMAGEN study. We validate our findings in marchigian sardinian (msP) alcohol-preferring rats that are genetically selected for increased alcohol drinking and stress sensitivity.

    RESULTS: We found that low methylation levels in intron 1 of OPRL1 are associated with higher psychosocial stress and higher frequency of binge drinking, an effect mediated by OPRL1 methylation. In individuals with low methylation of OPRL1, frequency of binge drinking is associated with stronger BOLD response in the ventral striatum during reward anticipation. In msP rats, we found that stress results in increased alcohol intake and decreased methylation of OPRL1 in the nucleus accumbens.

    CONCLUSIONS: Our findings describe an epigenetic mechanism that helps to explain how psychosocial stress influences risky alcohol consumption and reward processing, thus contributing to the elucidation of biological mechanisms underlying risk for substance abuse.

  • 59. Ruggeri, Barbara
    et al.
    Nymberg, Charlotte
    Vuoksimaa, Eero
    Lourdusamy, Anbarasu
    Wong, Cybele P.
    Carvalho, Fabiana M.
    Jia, Tianye
    Cattrell, Anna
    Macare, Christine
    Banaschewski, Tobias
    Barker, Gareth J.
    Bokde, Arun L. W.
    Bromberg, Uli
    Buechel, Christian
    Conrad, Patricia J.
    Fauth-Buehler, Mira
    Flor, Herta
    Frouin, Vincent
    Gallinat, Juergen
    Garavan, Hugh
    Gowland, Penny
    Heinz, Andreas
    Ittermann, Bernd
    Martinot, Jean-Luc
    Nees, Frauke
    Pausova, Zdenka
    Paus, Tomas
    Rietschel, Marcella
    Robbins, Trevor
    Smolka, Michael N.
    Spanagel, Rainer
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mill, Jonathan
    Sommer, Wolfgang H.
    Rose, Richard J.
    Yan, Jia
    Aliey, Fazil
    Dick, Danielle
    Kaprio, Jaakko
    Desrivieres, Sylvane
    Schumann, Gunter
    Association of Protein Phosphatase PPM1G With Alcohol Use Disorder and Brain Activity During Behavioral Control in a Genome-Wide Methylation Analysis2015In: American Journal of Psychiatry, ISSN 0002-953X, E-ISSN 1535-7228, Vol. 172, no 6, p. 543-552Article in journal (Refereed)
    Abstract [en]

    Objective: The genetic component of alcohol use disorder is substantial, but monozygotic twin discordance indicates a role for nonheritable differences that could be mediated by epigenetics. Despite growing evidence associating epigenetics and psychiatric disorders, it is unclear how epigenetics, particularly DNA methylation, relate to brain function and behavior, including drinking behavior. Method: The authors carried out a genome-wide analysis of DNA methylation of 18 monozygotic twin pairs discordant for alcohol use disorder and validated differentially methylated regions. After validation, the authors characterized these differentially methylated regions using personality trait assessment and functional MRI in a sample of 499 adolescents. Results: Hypermethylation in the 3'-protein-phosphatase-1G (PPM1G) gene locus was associated with alcohol use disorder. The authors found association of PPM1G hypermethylation with early escalation of alcohol use and increased impulsiveness. They also observed association of PPM1G hypermethylation with increased blood-oxygen-level-dependent response in the right subthalamic nucleus during an impulsiveness task. Conclusions: Overall, the authors provide first evidence for an epigenetic marker associated with alcohol consumption and its underlying neurobehavioral phenotype.

  • 60.
    Sarkisyan, Daniil
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bazov, Igor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Watanabe, Hiroyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kononenko, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Schumann, Gunter
    Kings Coll London, Inst Psychiat, London, England..
    Yakovleva, Tatiana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Damaged reward areas in human alcoholics: neuronal proportion decline and astrocyte activation2017In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 133, no 3, p. 485-487Article in journal (Refereed)
  • 61.
    Sarkisyan, Daniil
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bazov, Igor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Yakovleva, Tatiana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    EPIGENOME IN THE BRAIN OF HUMAN ALCOHOLICS: GENETICALLY-REGULATED TRAJECTORIES OF DNA METHYLATION2015In: Alcohol and Alcoholism, ISSN 0735-0414, E-ISSN 1464-3502, Vol. 50Article in journal (Other academic)
  • 62.
    Sarkisyan, Daniil
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hussain, Muhammad Zubair
    Watanabe, Hiroyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kononenko, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bazov, Igor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Zhou, Xingwu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Yamskova, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Krishtal, Oleg
    Karpyak, Victor
    Yakovleva, Tatiana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Downregulation of the endogenous opioid peptides in the dorsal striatum of human alcoholics2015In: Frontiers in Cellular Neuroscience, ISSN 1662-5102, E-ISSN 1662-5102, Vol. 9, article id 187Article in journal (Refereed)
    Abstract [en]

    The endogenous opioid peptides dynorphins and enkephalins may be involved in brain-area specific synaptic adaptations relevant for different stages of an addiction cycle. We compared the levels of prodynorphin (PDYN) and proenkephalin (PENK) mRNAs (by qRT-PCR), and dynorphins and enkephalins (by radioimmunoassay) in the caudate nucleus and putamen between alcoholics and control subjects. We also evaluated whether PDYN promoter variant rs1997794 associated with alcoholism affects PDYN expression. Postmortem specimens obtained from 24 alcoholics and 26 controls were included in final statistical analysis. PDYN mRNA and Met-enkephalin-Arg-Phe, a marker of PENK were downregulated in the caudate of alcoholics, while PDYN mRNA and Leu-enkephalin-Arg, a marker of PDYN were decreased in the putamen of alcoholics carrying high risk rs1997794 C allele. Downregulation of opioid peptides in the dorsal striatum may contribute to development of alcoholism including changes in goal directed behavior and formation of a compulsive habit in alcoholics.

  • 63. Schumann, Gunter
    et al.
    Coin, Lachlan J.
    Lourdusamy, Anbarasu
    Charoen, Pimphen
    Berger, Karen H.
    Stacey, David
    Desrivieres, Sylvane
    Aliev, Fazil A.
    Khan, Anokhi A.
    Amin, Najaf
    Aulchenko, Yurii S.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bakker, Stephan J.
    Balkau, Beverley
    Beulens, Joline W.
    Bilbao, Ainhoa
    de Boer, Rudolf A.
    Beury, Delphine
    Bots, Michiel L.
    Breetvelt, Elemi J.
    Cauchi, Stephane
    Cavalcanti-Proenca, Christine
    Chambers, John C.
    Clarke, Toni-Kim
    Dahmen, Norbert
    de Geus, Eco J.
    Dick, Danielle
    Ducci, Francesca
    Easton, Alanna
    Edenberg, Howard J.
    Esk, Tonu
    Fernandez-Medarde, Alberto
    Foroud, Tatiana
    Freimer, Nelson B.
    Girault, Jean-Antoine
    Grobbee, Diederick E.
    Guarrera, Simonetta
    Gudbjartsson, Daniel F.
    Hartikainen, Anna-Liisa
    Heath, Andrew C.
    Hesselbrock, Victor
    Hofman, Albert
    Hottenga, Jouke-Jan
    Isohanni, Matti K.
    Kaprio, Jaakko
    Khaw, Kay-Tee
    Kuehnel, Brigitte
    Laitinen, Jaana
    Lobbens, Stephane
    Luan, Jian'an
    Mangino, Massimo
    Maroteaux, Matthieu
    Matullo, Giuseppe
    McCarthy, Mark I.
    Mueller, Christian
    Navis, Gerjan
    Numans, Mattijs E.
    Nunez, Alejandro
    Nyholt, Dale R.
    Onland-Moret, Charlotte N.
    Oostra, Ben A.
    O'Reilly, Paul F.
    Palkovits, Miklos
    Penninx, Brenda W.
    Polidoro, Silvia
    Pouta, Anneli
    Prokopenko, Inga
    Ricceri, Fulvio
    Santos, Eugenio
    Smit, Johannes H.
    Soranzo, Nicole
    Song, Kijoung
    Sovio, Ulla
    Stumvoll, Michael
    Surakk, Ida
    Thorgeirsson, Thorgeir E.
    Thorsteinsdottir, Unnur
    Troakes, Claire
    Tyrfingsson, Thorarinn
    Toenjes, Anke
    Uiterwaal, Cuno S.
    Uitterlinden, Andre G.
    van der Harst, Pim
    van der Schouw, Yvonne T.
    Staehlin, Oliver
    Vogelzangs, Nicole
    Vollenweider, Peter
    Waeber, Gerard
    Wareham, Nicholas J.
    Waterworth, Dawn M.
    Whitfield, John B.
    Wichmann, Erich H.
    Willemsen, Gonneke
    Witteman, Jacqueline C.
    Yuan, Xin
    Zhai, Guangju
    Zhao, Jing H.
    Zhang, Weihua
    Martin, Nicholas G.
    Metspalu, Andres
    Doering, Angela
    Scott, James
    Spector, Tim D.
    Loos, Ruth J.
    Boomsma, Dorret I.
    Mooser, Vincent
    Peltonen, Leena
    Stefansson, Kari
    van Duijn, Cornelia M.
    Vineis, Paolo
    Sommer, Wolfgang H.
    Kooner, Jaspal S.
    Spanagel, Rainer
    Heberlein, Ulrike A.
    Jarvelin, Marjo-Riitta
    Elliott, Paul
    Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 17, p. 7119-7124Article in journal (Refereed)
    Abstract [en]

    Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of similar to 2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene (AUTS2) was associated with alcohol consumption at genome-wide significance (P = 4 x 10(-8) to P = 4 x 10(-9)). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples (P = 0.026) and significant (P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Downregulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila (P < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.

  • 64.
    Schumann, Gunter
    et al.
    Kings Coll London, MRC, Inst Psychiat Psychol & Neurosci, Social Genet & Dev Psychiat Ctr, London SE5 8AF, England..
    Liu, Chunyu
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, Div Intramural Res, Bethesda, MD 20824 USA.;Boston Univ, Sch Publ, Dept Biostat, Boston, MA 02118 USA..
    O'Reilly, Paul
    Kings Coll London, MRC, Inst Psychiat Psychol & Neurosci, Social Genet & Dev Psychiat Ctr, London SE5 8AF, England..
    Gao, He
    Imperial Coll London, Dept Epidemiol & Biostat, Sch Publ Hlth, London W2 1PG, England.;Imperial Coll London, MRC, Publ Hlth England Ctr Environm & Hlth, London W2 1PG, England..
    Song, Parkyong
    Univ Texas Southwestern Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA.;Univ Texas Southwestern Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA..
    Xu, Bing
    Kings Coll London, MRC, Inst Psychiat Psychol & Neurosci, Social Genet & Dev Psychiat Ctr, London SE5 8AF, England..
    Ruggeri, Barbara
    Kings Coll London, MRC, Inst Psychiat Psychol & Neurosci, Social Genet & Dev Psychiat Ctr, London SE5 8AF, England..
    Amin, Najaf
    Erasmus MC, Genet Epidemiol Unit, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands..
    Jia, Tianye
    Kings Coll London, MRC, Inst Psychiat Psychol & Neurosci, Social Genet & Dev Psychiat Ctr, London SE5 8AF, England..
    Preis, Sarah
    Boston Univ, Sch Publ, Dept Biostat, Boston, MA 02118 USA..
    Lepe, Marcelo Segura
    Imperial Coll London, Dept Epidemiol & Biostat, Sch Publ Hlth, London W2 1PG, England.;Bayer Pharma AG, Sect Bioinformat, D-13342 Berlin, Germany..
    Akira, Shizuo
    Osaka Univ, World Premier Int Immunol Frontier Res Ctr, Microbial Dis Res Inst, Lab Host Def, Osaka 5650871, Japan..
    Barbieri, Caterina
    San Raffaele Res Inst, Div Genet & Cell Biol, I-20132 Milan, Italy..
    Baumeister, Sebastian
    Univ Med Greifswald, Inst Community Med, D-17475 Greifswald, Germany.;Univ Regensburg, Dept Epidemiol & Prevent Med, D-93053 Regensburg, Germany..
    Cauchi, Stephane
    Univ Lille 2, European Genom Inst Diabet, Lille Pasteur Inst, CNRS,UMR 8199, F-59000 Lille, France..
    Clarke, Toni-Kim
    Univ Edinburgh, Div Psychiat, Edinburgh EH10 5HF, Midlothian, Scotland..
    Enroth, Stefan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Fischer, Krista
    Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia..
    Hallfors, Jenni
    Univ Helsinki, Inst Mol Med, Helsinki 00290, Finland..
    Harris, Sarah E.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland.;Univ Edinburgh, Ctr Genom & Expt Med, Edinburgh EH4 2XU, Midlothian, Scotland..
    Hieber, Saskia
    Friedrich Alexander Univ Erlangen Nuremberg, Dept Psychiat & Psychotherapy, D-91054 Erlangen, Germany..
    Hofer, Edith
    Med Univ Graz, Clin Div Neurogeriatr, Dept Neurol, A-8036 Graz, Austria.;Med Univ Graz, Inst Med Informat Stat & Documentat, A-8036 Graz, Austria..
    Hottenga, Jouke-Jan
    Vrije Univ Amsterdam, Dept Biol Psychol, NL-1081 BT Amsterdam, Netherlands.;EMGO Inst Hlth & Care Res, NL-1081 BT Amsterdam, Netherlands..
    Johansson, Åsa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Joshi, PeterK.
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh EH8 9AG, Midlothian, Scotland..
    Kaartinen, Niina
    Natl Inst Hlth & Welf, Helsinki 00271, Finland..
    Laitinen, Jaana
    Finnish Inst Occupat Hlth, Quantified Employee Unit, Helsinki 00250, Finland..
    Lemaitre, Rozenn
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA..
    Loukola, Anu
    Univ Helsinki, Inst Mol Med, Helsinki 00290, Finland.;Univ Helsinki, Dept Publ Hlth, FIN-00014 Helsinki, Finland..
    Luan, Jian'an
    Univ Cambridge, Sch Clin Med, MRC, Epidemiol Unit,Inst Metab Sci, Cambridge CB2 0QQ, England..
    Lyytikainen, Leo-Pekka
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Sch Med, Tampere 33520, Finland..
    Mangino, Massimo
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England.;Guys & St Thomas Fdn Trust, Natl Inst Hlth Res, Biomed Res Ctr, London SE1 9RT, England..
    Manichaikul, Ani
    Univ Virginia, Ctr Publ Hlth Genom, Dept Publ Hlth Sci, Charlottesville, VA 22903 USA.;Univ Virginia, Biostat Sect, Dept Publ Hlth Sci, Charlottesville, VA 22903 USA..
    Mbarek, Hamdi
    Vrije Univ Amsterdam, Dept Biol Psychol, NL-1081 BT Amsterdam, Netherlands.;EMGO Inst Hlth & Care Res, NL-1081 BT Amsterdam, Netherlands..
    Milaneschi, Yuri
    Vrije Univ Amsterdam, Inst Hlth & Care Res EMGO, Inst Hlth & Care Res, Dept Psychiat,Univ Med Ctr,Geestelijke Gezondheid, NL-1081 HL Amsterdam, Netherlands.;Vrije Univ Amsterdam, Neurosci Campus Amsterdam, Univ Med Ctr, Geestelijke Gezondheids Zorg GGZ InGeest, NL-1081 HL Amsterdam, Netherlands..
    Moayyeri, Alireza
    Imperial Coll London, Dept Epidemiol & Biostat, Sch Publ Hlth, London W2 1PG, England.;UCL, Inst Hlth Informat, London NW1 2DA, England.;UCL, Inst Hlth Informat, Farr Inst Hlth Informat Res, London NW1 2DA, England..
    Mukamal, Kenneth
    Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA.;Harvard Med Sch, Boston, MA 02215 USA..
    Nelson, Christopher
    Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England.;Glenfield Hosp, Natl Inst Hlth Res, Leicester Cardiovasc Biomed Res Unit, Leicester LE3 9QP, Leics, England..
    Nettleton, Jennifer
    Univ Texas Hlth Sci Ctr Houston, Div Epidemiol Human Genet & Environm Sci, Houston, TX 77225 USA..
    Partinen, Eemil
    Univ Tartu, Fac Med, EE-50411 Tartu, Estonia..
    Rawal, Rajesh
    Helmholtz Zentrum Munchen, Dept Mol Epidemiol, Inst Epidemiol 2, D-85764 Neuherberg, Germany..
    Robino, Antonietta
    Ist Ricovero & Cura Carattere Sci IRCCS Burlo Gar, Inst Maternal & Child Hlth, I-34137 Trieste, Italy..
    Rose, Lynda
    Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA..
    Sala, Cinzia
    San Raffaele Res Inst, Div Genet & Cell Biol, I-20132 Milan, Italy..
    Satoh, Takashi
    Osaka Univ, World Premier Int Immunol Frontier Res Ctr, Microbial Dis Res Inst, Lab Host Def, Osaka 5650871, Japan..
    Schmidt, Reinhold
    Med Univ Graz, Clin Div Neurogeriatr, Dept Neurol, A-8036 Graz, Austria..
    Schrautz, Katharina
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh EH8 9AG, Midlothian, Scotland..
    Scott, Robert
    Univ Cambridge, Sch Clin Med, MRC, Epidemiol Unit, Cambridge CB2 0QQ, England..
    Smith, Albert Vernon
    Iceland Heart Assoc, Res Inst, IS-201 Kopavogur, Iceland..
    Starr, John M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland.;Univ Edinburgh, Alzheimer Scotland Res Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland..
    Teumer, Alexander
    Univ Med Greifswald, Inst Community Med, D-17475 Greifswald, Germany.;Univ Med Greifswald, Interfac Inst Genet & Funct Genom, D-17475 Greifswald, Germany..
    Trompet, Stella
    Leiden Univ, Med Ctr, Dept Cardiol, NL-2300 RC Leiden, Netherlands.;Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, NL-2300 RC Leiden, Netherlands..
    Uitterlinden, Andre G.
    Erasmus MC, Dept Internal Med, NL-3015 CN Rotterdam, Netherlands.;Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands..
    Venturini, Cristina
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England..
    Vergnaud, Anne-Claire
    Imperial Coll London, Dept Epidemiol & Biostat, Sch Publ Hlth, London W2 1PG, England..
    Verweij, Niek
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9700 RB Groningen, Netherlands..
    Vitart, Veronique
    Univ Edinburgh, Western Gen Hosp, MRC, Human Genet Unit,Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland..
    Vuckovic, Dragana
    Univ Trieste, Dept Med Sci, I-34149 Trieste, Italy..
    Wedenoja, Juho
    Univ Helsinki, Dept Publ Hlth, FIN-00014 Helsinki, Finland..
    Yengo, Loic
    Univ Lille 2, European Genom Inst Diabet, Lille Pasteur Inst, CNRS,UMR 8199, F-59000 Lille, France..
    Yu, Bing
    Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Houston, TX 77225 USA.;Univ Texas Hlth Sci Ctr Houston, Div Epidemiol, Houston, TX 77225 USA..
    Zhang, Weihua
    Imperial Coll London, Dept Epidemiol & Biostat, Sch Publ Hlth, London W2 1PG, England.;Ealing Gen Hosp, Dept Cardiol, Southall UB1 3HW, Middx, England..
    Zhao, Jing Hua
    Univ Cambridge, Sch Clin Med, MRC, Epidemiol Unit, Cambridge CB2 0QQ, England..
    Boomsma, Dorret I.
    Vrije Univ Amsterdam, Dept Biol Psychol, NL-1081 BT Amsterdam, Netherlands.;EMGO Inst Hlth & Care Res, NL-1081 BT Amsterdam, Netherlands..
    Chambers, John
    Imperial Coll London, Dept Epidemiol & Biostat, Sch Publ Hlth, London W2 1PG, England.;Ealing Gen Hosp, Dept Cardiol, Southall UB1 3HW, Middx, England.;Imperial Coll Healthcare Natl Hlth Serv Trust, London W12 0HS, England..
    Chasman, Daniel I.
    Harvard Med Sch, Boston, MA 02215 USA.;Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA..
    Daniela, Toniolo
    San Raffaele Res Inst, Div Genet & Cell Biol, I-20132 Milan, Italy..
    de Geus, Eco
    Vrije Univ Amsterdam, Dept Biol Psychol, NL-1081 BT Amsterdam, Netherlands.;EMGO Inst Hlth & Care Res, NL-1081 BT Amsterdam, Netherlands..
    Deary, Ian
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland.;Univ Edinburgh, Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland..
    Eriksson, Johan G.
    Natl Inst Hlth & Welf, Helsinki 00271, Finland.;Univ Helsinki, Dept Gen Practice & Primary Hlth Care, FIN-00014 Helsinki, Finland.;Univ Helsinki, Cent Hosp, Unit Gen Practice, FIN-00014 Helsinki, Finland.;Publ Hlth Res, Folkhalsan Res Ctr, Helsinki 00290, Finland.;Vasa Cent Hosp, Vaasa 65130, Finland..
    Esko, Tonu
    Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia..
    Eulenburg, Volker
    Friedrich Alexander Univ Erlangen Nuremberg, Inst Biochem & Mol Med, D-91054 Erlangen, Germany..
    Franco, Oscar H.
    Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands..
    Froguel, Philippe
    Univ Lille 2, European Genom Inst Diabet, Lille Pasteur Inst, CNRS,UMR 8199, F-59000 Lille, France.;Imperial Coll London, Dept Genom Common Dis, Sch Publ Hlth, London W12 0HR, England..
    Gieger, Christian
    Helmholtz Zentrum Munchen, Dept Mol Epidemiol, Inst Epidemiol 2, D-85764 Neuherberg, Germany..
    Grabe, Hans J.
    Univ Med Greifswald, Dept Psychiat & Psychotherapy, D-17475 Greifswald, Germany..
    Gudnason, Vilmundur
    Iceland Heart Assoc, Res Inst, IS-201 Kopavogur, Iceland.;Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland..
    Gyllensten, Ulf B.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Harris, Tamara B.
    NIA, NIH, Bethesda, MD 20892 USA..
    Hartikainen, Anna-Liisa
    Oulu Univ Hosp, Dept Obstet & Gynecol, Oulu 90029, Finland.;Univ Oulu, MRC, Oulu 90014, Finland.;Oulu Univ Hosp, Unit Primary Care, Oulu 90220, Finland..
    Heath, Andrew C.
    Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA..
    Hocking, Lynne
    Univ Aberdeen, Inst Med Sci, Aberdeen AB25 2ZD, Scotland..
    Hofman, Albert
    Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands..
    Huth, Cornelia
    German Res Ctr Environm Hlth GmbH, Inst Epidemiol 2, Helmholtz Zentrum Munchen, D-85764 Neuherberg, Germany..
    Jarvelin, Marjo-Riitta
    Imperial Coll London, Dept Epidemiol & Biostat, Sch Publ Hlth, London W2 1PG, England.;Erasmus MC, Dept Internal Med, NL-3015 CN Rotterdam, Netherlands.;Oulu Univ Hosp, Unit Primary Care, Oulu 90220, Finland.;Univ Oulu, Fac Med, Ctr Life Course Epidemiol, FI-90014 Oulu, Finland.;Univ Oulu, Bioctr Oulu, FI-90014 Oulu, Finland..
    Jukema, J. Wouter
    Leiden Univ, Med Ctr, Dept Cardiol, NL-2300 RC Leiden, Netherlands..
    Kaprio, Jaakko
    Univ Helsinki, Inst Mol Med, Helsinki 00290, Finland.;Natl Inst Hlth & Welf, Helsinki 00271, Finland.;Univ Helsinki, Dept Publ Hlth, FIN-00014 Helsinki, Finland..
    Kooner, Jaspal S.
    Ealing Gen Hosp, Dept Cardiol, Southall UB1 3HW, Middx, England.;Imperial Coll Healthcare Natl Hlth Serv Trust, London W12 0HS, England.;Imperial Coll London, Hammersmith Hosp, Natl Heart & Lung Inst, Fac Med,Cardiovasc Sci, London W12 0NN, England..
    Kutalik, Zoltan
    Ctr Hosp Univ Vaudoise, Inst Social & Prevent Med, CH-1010 Lausanne, Switzerland..
    Lahti, Jari
    Publ Hlth Res, Folkhalsan Res Ctr, Helsinki 00290, Finland.;Univ Helsinki, Coll Adv Studies, FIN-00014 Helsinki, Finland.;Univ Helsinki, Inst Behav Sci, FIN-00014 Helsinki, Finland..
    Langenberg, Claudia
    Univ Cambridge, Sch Clin Med, MRC, Epidemiol Unit,Inst Metab Sci, Cambridge CB2 0QQ, England..
    Lehtimaki, Terho
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Sch Med, Tampere 33520, Finland..
    Liu, Yongmei
    Wake Forest Sch Med, Wake Forest Sch Med, Dept Epidemiol & Prevent, Publ Hlth Sci, Winston Salem, NC 27157 USA..
    Madden, Pamela A. F.
    Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA..
    Martin, Nicholas
    Queensland Inst Med Res, Berghofer Med Res Inst, Genet Epidemiol, Brisbane, Qld 4029, Australia..
    Morrison, Alanna
    Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Houston, TX 77225 USA..
    Penninx, Brenda
    Vrije Univ Amsterdam, Inst Hlth & Care Res EMGO, Inst Hlth & Care Res, Dept Psychiat,Univ Med Ctr,Geestelijke Gezondheid, NL-1081 HL Amsterdam, Netherlands.;Vrije Univ Amsterdam, Neurosci Campus Amsterdam, Univ Med Ctr, Geestelijke Gezondheids Zorg GGZ InGeest, NL-1081 HL Amsterdam, Netherlands..
    Pirastu, Nicola
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh EH8 9AG, Midlothian, Scotland.;Univ Trieste, Dept Med Sci, I-34149 Trieste, Italy..
    Psaty, Bruce
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA.;Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.;Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA.;Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA 98101 USA..
    Raitakari, Olli
    Univ Turku, Dept Clin Physiol & Nucl Med, Turku Univ Hosp, FIN-20520 Turku, Finland.;Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, FIN-20520 Turku, Finland..
    Ridker, Paul
    Harvard Med Sch, Boston, MA 02215 USA.;Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA..
    Rose, Richard
    Indiana Univ, Dept Psychol & Brain Sci, Bloomington, IN 47405 USA..
    Rotter, Jerome I.
    Univ Calif Los Angeles, Los Angeles Biomed Res Inst Harbor, Med Ctr, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA..
    Samani, Nilesh J.
    Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England.;Glenfield Hosp, Natl Inst Hlth Res, Leicester Cardiovasc Biomed Res Unit, Leicester LE3 9QP, Leics, England..
    Schmidt, Helena
    Med Univ Graz, Inst Mol Biol & Biochem, Ctr Mol Med, A-8010 Graz, Austria..
    Spector, Tim D.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England..
    Stott, David
    Univ Glasgow, Inst Cardiovasc & Med Sci, Fac Med, Glasgow G31 2ER, Lanark, Scotland..
    Strachan, David
    St Georges Univ London, Populat Hlth Res Inst, London SW17 0RE, England..
    Tzoulaki, Ioanna
    Imperial Coll London, Dept Epidemiol & Biostat, Sch Publ Hlth, London W2 1PG, England.;Imperial Coll London, MRC, Publ Hlth England Ctr Environm & Hlth, London W2 1PG, England.;Univ Ioannina, Dept Hyg & Epidemiol, Med Sch, GR-45110 Ioannina, Greece..
    van der Harst, Pim
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9700 RB Groningen, Netherlands.;Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands.;Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Interuniv Cardiol Inst Netherlands, NL-3511 GC Utrecht, Netherlands..
    van Duijn, Cornelia M.
    Erasmus MC, Genet Epidemiol Unit, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands..
    Marques-Vidal, Pedro
    Univ Lausanne Hosp, Dept Med, Internal Med, CH-1011 Lausanne, Switzerland..
    Vollenweider, Peter
    Univ Lausanne Hosp, Dept Med, Internal Med, CH-1011 Lausanne, Switzerland..
    Wareham, Nicholas J.
    Univ Cambridge, Sch Clin Med, MRC, Epidemiol Unit, Cambridge CB2 0QQ, England..
    Whitfield, John B.
    Queensland Inst Med Res, Berghofer Med Res Inst, Genet Epidemiol, Brisbane, Qld 4029, Australia..
    Wilson, James
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh EH8 9AG, Midlothian, Scotland.;Univ Edinburgh, Western Gen Hosp, MRC, Human Genet Unit,Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland..
    Wolffenbuttel, Bruce
    Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, NL-9700 RB Groningen, Netherlands..
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Evangelou, Evangelos
    Imperial Coll London, Dept Epidemiol & Biostat, Sch Publ Hlth, London W2 1PG, England.;Univ Ioannina, Dept Hyg & Epidemiol, Med Sch, GR-45110 Ioannina, Greece..
    Liu, Yun
    Minist Educ, Key Lab Metab & Mol Med, Shanghai 200032, Peoples R China.;Fudan Univ, Shanghai Med Coll, Dept Biochem & Mol Biol, Shanghai 200032, Peoples R China..
    Rice, Kenneth M.
    Univ Washington, Dept Biostat, Seattle, WA 98195 USA..
    Desrivieres, Sylvane
    Kings Coll London, MRC, Inst Psychiat Psychol & Neurosci, Social Genet & Dev Psychiat Ctr, London SE5 8AF, England..
    Kliewer, Steven A.
    Univ Texas Southwestern Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA.;Univ Texas Southwestern Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA..
    Mangelsdorf, David J.
    Univ Texas Southwestern Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA.;Univ Texas Southwestern Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA..
    Muller, Christian P.
    Friedrich Alexander Univ Erlangen Nuremberg, Dept Psychiat & Psychotherapy, D-91054 Erlangen, Germany..
    Levy, Daniel
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, Div Intramural Res, Bethesda, MD 20824 USA..
    Elliott, Paul
    Imperial Coll London, Dept Epidemiol & Biostat, Sch Publ Hlth, London W2 1PG, England.;Imperial Coll London, MRC, Publ Hlth England Ctr Environm & Hlth, London W2 1PG, England..
    KLB is associated with alcohol drinking, and its gene product beta-Klotho is necessary for FGF21 regulation of alcohol preference2016In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 50, p. 14372-14377Article in journal (Refereed)
    Abstract [en]

    Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified beta-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 x 10(-12)). beta-Klotho is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. We show that brain-specific beta-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver-brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.

  • 65. Sirohi, Sunil
    et al.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Walker, Brendan M
    Alcohol-induced plasticity in the dynorphin/kappa-opioid receptor system2012In: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 5, no Artcle 95, p. 1-12Article in journal (Refereed)
    Abstract [en]

    Alcoholism is a chronic relapsing disorder characterized by continued alcohol use despite numerous adverse consequences. Alcohol has been shown to interact with numerous neurotransmitter systems to exert its pharmacological effects. The endogenous opioid system (EOS) has been strongly implicated in the positive and negative reinforcing effects of alcohol. Traditionally recognized as dysphoric/anhedonic in nature, the dynorphin/kappa-opioid receptor (DYN/KOR) system has recently received considerable attention due to evidence suggesting that an upregulated DYN/KOR system may be a critical contributor to the complex factors that result in escalated alcohol consumption once dependent. The present review will discuss alcohol-induced plasticity in the DYN/KOR system and how these neuroadaptations could contribute to excessive alcohol seeking and consumption.

  • 66.
    Smeets, Cleo J. L. M.
    et al.
    Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands..
    Jezierska, Justyna
    Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands..
    Watanabe, Hiroyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Duarri, Anna
    Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands..
    Fokkens, Michiel R.
    Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands..
    Meijer, Michel
    Univ Groningen, Univ Med Ctr Groningen, Dept Med Physiol, Groningen, Netherlands..
    Zhou, Qin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Yakovleva, Tania
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Boddeke, Erik
    Univ Groningen, Univ Med Ctr Groningen, Dept Med Physiol, Groningen, Netherlands..
    den Dunnen, Wilfred
    Univ Groningen, Univ Med Ctr Groningen, Dept Pathol, Groningen, Netherlands..
    van Deursen, Jan
    Mayo Clin, Dept Paediat & Adolescent Med, Rochester, MN USA..
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kampinga, Harm H.
    Univ Groningen, Univ Med Ctr Groningen, Dept Cell Biol, Groningen, Netherlands..
    van de Sluis, Bart
    Univ Groningen, Univ Med Ctr Groningen, Dept Paediat, Mol Genet Sect, Groningen, Netherlands..
    Verbeek, Dineke S.
    Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands..
    Elevated mutant dynorphin A causes Purkinje cell loss and motor dysfunction in spinocerebellar ataxia type 232015In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 138, p. 2537-2552Article in journal (Refereed)
    Abstract [en]

    Spinocerebellar ataxia type 23 is caused by mutations in PDYN, which encodes the opioid neuropeptide precursor protein, prodynorphin. Prodynorphin is processed into the opioid peptides, a-neoendorphin, and dynorphins A and B, that normally exhibit opioid-receptor mediated actions in pain signalling and addiction. Dynorphin A is likely a mutational hotspot for spinocerebellar ataxia type 23 mutations, and in vitro data suggested that dynorphin A mutations lead to persistently elevated mutant peptide levels that are cytotoxic and may thus play a crucial role in the pathogenesis of spinocerebellar ataxia type 23. To further test this and study spinocerebellar ataxia type 23 in more detail, we generated a mouse carrying the spinocerebellar ataxia type 23 mutation R212W in PDYN. Analysis of peptide levels using a radioimmunoassay shows that these PDYN R212W mice display markedly elevated levels of mutant dynorphin A, which are associated with climber fibre retraction and Purkinje cell loss, visualized with immunohistochemical stainings. The PDYN R212W mice reproduced many of the clinical features of spinocerebellar ataxia type 23, with gait deficits starting at 3 months of age revealed by footprint pattern analysis, and progressive loss of motor coordination and balance at the age of 12 months demonstrated by declining performances on the accelerating Rotarod. The pathologically elevated mutant dynorphin A levels in the cerebellum coincided with transcriptionally dysregulated ionotropic and metabotropic glutamate receptors and glutamate transporters, and altered neuronal excitability. In conclusion, the PDYN R212W mouse is the first animal model of spinocerebellar ataxia type 23 and our work indicates that the elevated mutant dynorphin A peptide levels are likely responsible for the initiation and progression of the disease, affecting glutamatergic signalling, neuronal excitability, and motor performance. Our novel mouse model defines a critical role for opioid neuropeptides in spinocerebellar ataxia, and suggests that restoring the elevated mutant neuropeptide levels can be explored as a therapeutic intervention.

  • 67.
    Smeets, Cleo J. L. M.
    et al.
    Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands..
    Zmorzynska, Justyna
    Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands..
    Melo, Manuel N.
    Univ Groningen, Groningen Biomol Sci & Biotechnol Inst, Ctr Life Sci, Groningen, Netherlands..
    Stargardt, Anita
    Acad Med Ctr, Dept Cell Biol & Histol, Amsterdam, Netherlands..
    Dooley, Colette
    Torrey Pines Inst Mol Studies, Port St Lucie, FL USA..
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    McLaughlin, Jay
    Univ Florida, Dept Pharmacodynam, Gainesville, FL 32610 USA..
    Sinke, Richard J.
    Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands..
    Marrink, Siewert-Jan
    Reits, Eric
    Acad Med Ctr, Dept Cell Biol & Histol, Amsterdam, Netherlands..
    Verbeek, Dineke S.
    Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands..
    Altered secondary structure of Dynorphin A associates with loss of opioid signalling and NMDA-mediated excitotoxicity in SCA232016In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 25, no 13, p. 2728-2737Article in journal (Refereed)
    Abstract [en]

    Spinocerebellar ataxia type 23 (SCA23) is caused by missense mutations in prodynorphin, encoding the precursor protein for the opioid neuropeptides alpha-neoendorphin, Dynorphin (Dyn) A and Dyn B, leading to neurotoxic elevated mutant Dyn A levels. Dyn A acts on opioid receptors to reduce pain in the spinal cord, but its cerebellar function remains largely unknown. Increased concentration of or prolonged exposure to Dyn A is neurotoxic and these deleterious effects are very likely caused by an N-methyl-D-aspartate-mediated non-opioidmechanism as Dyn A peptides were shown to bind NMDA receptors and potentiate their glutamate-evoked currents. In the present study, we investigated the cellular mechanisms underlying SCA23-mutant Dyn A neurotoxicity. We show that SCA23 mutations in the Dyn A-coding region disrupted peptide secondary structure leading to a loss of the N-terminal alpha-helix associated with decreased kappa-opioid receptor affinity. Additionally, the altered secondary structure led to increased peptide stability of R6W and R9C Dyn A, as these peptides showed marked degradation resistance, which coincided with decreased peptide solubility. Notably, L5S Dyn A displayed increased degradation and no aggregation. R6W and wt Dyn A peptides were most toxic to primary cerebellar neurons. For R6W Dyn A, this is likely because of a switch from opioid to NMDA-receptor signalling, while for wt Dyn A, this switch was not observed. We propose that the pathology of SCA23 results from converging mechanisms of loss of opioid-mediated neuroprotection and NMDA-mediated excitotoxicity.

  • 68.
    Sui, Ping
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Watanabe, Hiroyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Artemenko, Konstantin
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Sun, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Andersson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Neuropeptide imaging in rat spinal cord with MALDI-TOF MS: Method development for the application in pain-related disease studies2017In: European journal of mass spectrometry, ISSN 1469-0667, E-ISSN 1751-6838, Vol. 23, no 3, p. 105-115Article in journal (Refereed)
    Abstract [en]

    Spinal cord as a connection between brain and peripheral nervous system is an essential material for studying neural transmission, especially in pain-related research. This study was the first to investigate pain-related neuropeptide distribution in rat spinal cord using a matrix-assisted laser desorption ionization-time of flight imaging mass spectrometry (MALDI TOF MS) approach. The imaging workflow was evaluated and showed that MALDI TOF MS provides efficient resolution and robustness for neuropeptide imaging in rat spinal cord tissue. The imaging result showed that in naive rat spinal cord the molecular distribution of haeme, phosphatidylcholine, substance P and thymosin beta 4 were well in line with histological features. Three groups of pain-related neuropeptides, which are cleaved from prodynorphin, proenkephalin and protachykinin-1 proteins were detected. All these neuropeptides were found predominantly localized in the dorsal spinal cord and each group had unique distribution pattern. This study set the stage for future MALDI TOF MS application to elucidate signalling mechanism of pain-related diseases in small animal models.

  • 69.
    Sui, Ping
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Watanabe, Hiroyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ossipov, Michael
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Artemenko, Konstantin
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Proteomics of Neuropathic Pain: Proteins and Signaling Pathways Affected in a Rat Model2014In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 13, no 9, p. 3957-3965Article in journal (Refereed)
    Abstract [en]

    The myriad proteins may be involved in the mechanisms underlying the development and maintenance of neuropathic pain, an extremely disabling condition that originates from pathology of the nervous system. To address the mechanisms, we here analyzed proteins and cellular networks in the dorsal spinal cord mediating pain processing in a well-established rat model of neuropathic pain induced by spinal nerve ligation (SNL). Labeling-based proteomic methods together with high-resolution mass spectrometry for proteome analysis were applied. 38 proteins including synapsin 1 and microtubule-associated protein 2 were identified as differently expressed in the SNL group. Pathway analysis suggests that maladaptive changes in the levels of these proteins may contribute to abnormal synaptic transmission and neuronal intracellular signaling underlying the onset and development of neuropathic pain.

  • 70.
    Sui, Ping
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Watanabe, Hiroyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ossipov, Michael H.
    Porreca, Frank
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Artemenko, Konstantin
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Dimethyl-Labeling-Based Protein Quantification and Pathway Search: A Novel Method of Spinal Cord Analysis Applicable for Neurological Studies2013In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 12, no 5, p. 2245-2252Article in journal (Refereed)
    Abstract [en]

    In this paper we describe a simple, fast, and inexpensive approach for quantitative analysis of proteins originated from small central nervous system (CNS) samples, i.e., rat spinal cord. The presented sample preparation protocol and quantification results from isotope dimethyl labeling were statistically evaluated and approved as a reliable and robust method for animal model studies of neurological disorders. Combined with the biopathway analysis tool IPA, the method was applied for comparative analysis of proteins in the dorsal and ventral segments of the rat spinal cord. The results are in agreement with the previously published protein patterns in these tissues. A majority (73%) of proteins identified as “related with CNS development and functions” were found to be overexpressed in the dorsal section compared to the ventral segment. The pathway related to neuropathic pain was overrepresented in the dorsal tissue samples. The developed novel approach may be applied for analyses of the spinal cord mediated neurological dysfunctions and pathological pain.

  • 71.
    Tan-No, Koichi
    et al.
    Department of Pharmacology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
    Shimoda, Masakazu
    Department of Pharmacology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
    Watanabe, Kenya
    Department of Pharmacology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
    Nakagawasai, Osamu
    Department of Pharmacology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
    Niijima, Fukie
    Department of Pharmacology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
    Kanno, Syu-Ichi
    Department of Clinical Pharmacotherapeutics, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
    Ishikawa, Masaaki
    Department of Clinical Pharmacotherapeutics, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Tadano, Takeshi
    Department of Pharmacology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
    Involvement of the p53 tumor-suppressor protein in the development of antinociceptive tolerance to morphine2009In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 450, no 3, p. 365-368Article in journal (Refereed)
    Abstract [en]

    The present study was designed to determine whether the p53 tumor-suppressor protein is involved in the development of antinociceptive tolerance to morphine. When the doses of morphine (mg/kg per injection) were subcutaneously given into mice as pretreatment twice daily for 2 days (first day (30) and second day (60)), intrathecal (i.t.) administration of morphine (0.1nmol) was inactive due to antinociceptive tolerance in the 0.5% formalin test on the third day. Tolerance to i.t. morphine was significantly suppressed by i.t. injection of pifithrin-alpha (1 and 10nmol), an inhibitor of p53 activation, benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (Z-VAD-fmk) (1 and 10nmol), a non-selective caspase inhibitor, or N(G)-nitro-l-arginine methyl ester (l-NAME) (2 and 20nmol), a non-selective inhibitor of nitric oxide synthase, 5min before each morphine treatment during the induction, with none given on the test day. Moreover, p53 expression in the spinal cord had increased significantly 14h after the last morphine administration. These results indicate that the increased expression and activation of p53, and the nitric oxide and caspase systems related to p53 may contribute to the development of antinociceptive tolerance to morphine in the mouse spinal cord.

  • 72.
    Tan-No, Koichi
    et al.
    Department of Pharmacology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
    Takahashi, Hiroaki
    Department of Pharmacology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
    Nakagawasai, Osamu
    Department of Pharmacology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
    Niijima, Fukie
    Department of Pharmacology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
    Sakurada, Shinobu
    Department of Physiology and Anatomy, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Terenius, Lars
    Department of Clinical Neuroscience, Section of Alcohol and Drug Dependence Research, Karolinska Institute, Stockholm , Sweden.
    Tadano, Takeshi
    Department of Pharmacology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
    Nociceptive behavior induced by the endogenous opioid peptides dynorphins in uninjured mice: evidence with intrathecal N-ethylmaleimide inhibiting dynorphin degradation2009In: Advances in neuropharmacology / [ed] Bagetta G; Corasaniti MT; Sakurada T; Sakurada S, San Diego: Elsevier Academic Press , 2009, Vol. 85, p. 191-205Chapter in book (Refereed)
    Abstract [en]

    Dynorphins, the endogenous opioid peptides derived from prodynorphin may participate not only in the inhibition, but also in facilitation of spinal nociceptive transmission. However, the mechanism of pronociceptive dynorphin actions, and the comparative potential of prodynorphin processing products to induce these actions were not fully elucidated. In our studies, we examined pronociceptive effects of prodynorphin fragments dynorphins A and B and big dynorphin consisting of dynorphins A and B, and focused on the mechanisms underlying these effects. Our principal finding was that big dynorphin was the most potent pronociceptive dynorphin; when administered intrathecally into mice at extremely low doses (1-10fmol), big dynorphin produced nociceptive behavior through the activation of the NMDA receptor ion-channel complex by acting on the polyamine recognition site. We next examined whether the endogenous dynorphins participate in the spinal nociceptive transmission using N-ethylmaleimide (NEM) that blocks dynorphin degradation by inhibiting cysteine proteases. Similar to big dynorphin and dynorphin A, NEM produced nociceptive behavior mediated through inhibition of the degradation of endogenous dynorphins, presumably big dynorphin that in turn activates the NMDA receptor ion-channel complex by acting on the polyamine recognition site. Our findings support the notion that endogenous dynorphins are critical neurochemical mediators of spinal nociceptive transmission in uninjured animals. This chapter will review above-described phenomena and their mechanism.

  • 73.
    Taqi, Malik Mumtaz
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bazov, Igor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Watanabe, Hiroyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Yakovleva, Tatjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Prodynorphin promoter SNP associated with alcohol dependence forms noncanonical AP-1 binding site that may influence gene expression in human brain2011In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1385, p. 18-25Article in journal (Refereed)
    Abstract [en]

    Single nucleotide polymorphism (rs1997794) in promoter of the prodynorphin gene (PDYN) associated with alcohol-dependence may impact PDYN transcription in human brain. To address this hypothesis we analyzed PDYN mRNA levels in the dorsolateral prefrontal cortex (dl-PFC) and hippocampus, both involved in cognitive control of addictive behavior and PDYN promoter SNP genotype in alcohol-dependent and control human subjects. The principal component analysis suggested that PDYN expression in the dl-PFC may be related to alcoholism, while in the hippocampus may depend on the genotype. We also demonstrated that the T, low risk SNP allele resides within noncanonical AP-1-binding element that may be targeted by JUND and FOSS proteins, the dominant AP-1 constituents in the human brain. The T to C transition abrogated AP-1 binding. The impact of genetic variations on PDYN transcription may be relevant for diverse adaptive responses of this gene to alcohol.

  • 74.
    Taqi, Malik Mumtaz
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wärmländer, Sebastian K. T. S.
    Yamskova, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Madani, Fatemeh
    Bazov, Igor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Luo, Jinghui
    Zubarev, Roman
    Verbeek, Dineke
    Gräslund, Astrid
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Conformation Effects of CpG Methylation on Single-Stranded DNA Oligonucleotides: Analysis of the Opioid Peptide Dynorphin-Coding Sequences2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 6, p. e39605-Article in journal (Refereed)
    Abstract [en]

    Single-stranded DNA (ssDNA) is characterized by high conformational flexibility that allows these molecules to adopt a variety of conformations. Here we used native polyacrylamide gel electrophoresis (PAGE), circular dichroism (CD) spectroscopy and nuclear magnetic resonance (NMR) spectroscopy to show that cytosine methylation at CpG sites affects the conformational flexibility of short ssDNA molecules. The CpG containing 37-nucleotide PDYN (prodynorphin) fragments were used as model molecules. The presence of secondary DNA structures was evident from differences in oligonucleotide mobilities on PAGE, from CD spectra, and from formation of A-T, G-C, and non-canonical G-T base pairs observed by NMR spectroscopy. The oligonucleotides displayed secondary structures at 4 degrees C, and some also at 37 degrees C. Methylation at CpG sites prompted sequence-dependent formation of novel conformations, or shifted the equilibrium between different existing ssDNA conformations. The effects of methylation on gel mobility and base pairing were comparable in strength to the effects induced by point mutations in the DNA sequences. The conformational effects of methylation may be relevant for epigenetic regulatory events in a chromatin context, including DNA-protein or DNA-DNA recognition in the course of gene transcription, and DNA replication and recombination when double-stranded DNA is unwinded to ssDNA.

  • 75.
    Tay, Nicole
    et al.
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England.
    Macare, Christine
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England.
    Liu, Yun
    Fudan Univ, Dept Biochem & Mol Biol, MOE Key Lab Metab & Mol Med, Sch Basic Med Sci, Shanghai, Peoples R China.
    Ruggeri, Barbara
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England.
    Jia, Tianye
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England;Fudan Univ, Inst Sci & Technol Brain Inspired Intelligen, Shanghai, Peoples R China;Fudan Univ, Key Lab Computat Neurosci & Brain Inspired Intell, Minist Educ, Shanghai, Peoples R China.
    Chu, Congying
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England.
    Biondo, Francesca
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England.
    Ing, Alex
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England.
    Luo, Qiang
    Fudan Univ, Sch Life Sci, Shanghai, Peoples R China;Fudan Univ, Inst Sci & Technol Brain Inspired Intelligence, Shanghai, Peoples R China.
    Sarkisyan, Daniil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Banaschewski, Tobias
    Heidelberg Univ, Dept Child & Adolescent Psychiat & Psychotherapy, Cent Inst Mental Hlth, Mannheim, Germany.
    Barker, Gareth J.
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England.
    Bokde, Arun L. W.
    Trinity Coll Dublin, Discipline Psychiat, Sch Med, Dublin, Ireland;Trinity Coll Dublin, Trinity Coll, Inst Neurosci, Dublin, Ireland.
    Bromberg, Uli
    Univ Med Ctr Hamburg Eppendorf, Hamburg, Germany.
    Büchel, Christian
    Univ Med Ctr Hamburg Eppendorf, Hamburg, Germany.
    Quinlan, Erin Burke
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England.
    Desrivieres, Sylvane
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England.
    Flor, Herta
    Heidelberg Univ, Dept Cognit & Clin Neurosci, Cent Inst Mental Hlth, Med Fac Mannheim, Mannheim, Germany;Univ Mannheim, Dept Psychol, Sch Social Sci, Mannheim, Germany.
    Frouin, Vincent
    Univ Paris Saclay, NeuroSpin, Gif Sur Yvette, France.
    Garavan, Hugh
    Univ Vermont, Dept Psychiat, Burlington, VT USA;Univ Vermont, Dept Psychol, Burlington, VT 05405 USA.
    Gowland, Penny
    Univ Nottingham, Sir Peter Mansfield Imaging Ctr Sch Phys, Nottingham, England.
    Heinz, Andreas
    Univ Med Berlin, Charite, Dept Psychiat & Psychotherapy, Campus Charite Mitte, Berlin, Germany.
    Ittermann, Bernd
    Phys Tech Bundesanstalt, Berlin, Germany.
    Martinot, Jean-Luc
    Univ Paris 05, Univ Paris Sud Paris Saclay, Unit 1000 Neuroimaging & Psychiat, DIGITEO Labs,INSERM, Gif Sur Yvette, France;Cochin Hosp, Maison Solenn, Paris, France.
    Artiges, Eric
    Univ Paris Saclay, Univ Paris Sud, DIGITEO Labs, INSERM, Gif Sur Yvette, France;Orsay Hosp, Dept Psychiat, Orsay, France.
    Nees, Frauke
    Trinity Coll Dublin, Discipline Psychiat, Sch Med, Dublin, Ireland;Trinity Coll Dublin, Trinity Coll, Inst Neurosci, Dublin, Ireland;Heidelberg Univ, Dept Cognit & Clin Neurosci, Cent Inst Mental Hlth, Med Fac Mannheim, Mannheim, Germany;Heidelberg Univ, Dept Child & Adolescent Psychiat & Psychotherapy, Cent Inst Mental Hlth, Med Fac Mannheim, Mannheim, Germany;Nees German Res Fdn, Bonn, Germany.
    Orfanos, Dimitri Papadopoulos
    Univ Paris Saclay, NeuroSpin, Gif Sur Yvette, France.
    Paus, Tomas
    Univ Toronto, Bloorview Res Inst, Holland Bloorview Kids Rehabil, Hosp & Dept Psychol, Toronto, ON, Canada;Univ Toronto, Bloorview Res Inst, Holland Bloorview Kids Rehabil, Dept Psychiat, Toronto, ON, Canada.
    Poustka, Luise
    Univ Med Ctr Gottingen, Dept Child & Adolescent Psychiat & Psychotherapy, Gottingen, Germany;Med Univ Vienna, Clin Child & Adolescent Psychiat, Vienna, Austria.
    Hohmann, Sarah
    Heidelberg Univ, Dept Child & Adolescent Psychiat & Psychotherapy, Cent Inst Mental Hlth, Mannheim, Germany.
    Fröhner, Juliane H.
    Tech Univ Dresden, Dept Psychiat, Dresden, Germany;Tech Univ Dresden, Neuroimaging Ctr, Dresden, Germany.
    Smolka, Michael N.
    Tech Univ Dresden, Dept Psychiat, Dresden, Germany;Tech Univ Dresden, Neuroimaging Ctr, Dresden, Germany.
    Walter, Henrik
    Univ Med Berlin, Charite, Dept Psychiat & Psychotherapy, Campus Charite Mitte, Berlin, Germany.
    Whelan, Robert
    Trinity Coll Dublin, Sch Psychol, Dublin, Ireland;Trinity Coll Dublin, Global Brain Hlth Inst, Dublin, Ireland.
    Frieling, Helge
    Hannover Med Sch, Dept Psychiat Social Psychiat & Psychotherapy, Hannover, Germany.
    Bleich, Stefan
    Hannover Med Sch, Dept Psychiat Social Psychiat & Psychotherapy, Hannover, Germany.
    Barker, Edward D.
    Kings Coll London, Ctr Neuroimaging Sci, Inst Psychiat Psychol & Neurosci, London, England.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rüegg, Joelle
    Karolinska Inst, Dept Clin Neurosci, Ctr Mol Med, Stockholm, Sweden.
    Ekström, Tomas J.
    Karolinska Inst, Dept Clin Neurosci, Ctr Mol Med, Stockholm, Sweden.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schumann, Gunter
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England.
    Allele-Specific Methylation of SPDEF: A Novel Moderator of Psychosocial Stress and Substance Abuse2019In: American Journal of Psychiatry, ISSN 0002-953X, E-ISSN 1535-7228, Vol. 176, no 2, p. 146-155Article in journal (Refereed)
    Abstract [en]

    Objective: Psychosocial stress is a key risk factor for substance abuse among adolescents. Recently, epigenetic processes such as DNA methylation have emerged as potential mechanisms that could mediate this relationship. The authors conducted a genome-wide methylation analysis to investigate whether differentially methylated regions are associated with psychosocial stress in an adolescent population.

    Methods: A methylome-wide analysis of differentially methylated regions was used to examine a sample of 1,287 14-year-old adolescents (50.7% of them female) from the European IMAGEN study. The Illumina 450k array was used to assess DNA methylation, pyrosequencing was used for technical replication, and linear regression analyses were used to identify associations with psychosocial stress and substance use (alcohol and tobacco). Findings were replicated by pyrosequencing a test sample of 413 participants from the IMAGEN study.

    Results: Hypermethylation in the sterile alpha motif/pointed domain containing the ETS transcription factor (SPDEF) gene locus was associated with a greater number of stressful life events in an allele-dependent way. Among individuals with the minor G-allele, SPDEF methylation moderated the association between psychosocial stress and substance abuse. SPDEF methylation interacted with lifetime stress in gray matter volume in the right cuneus, which in turn was associated with the frequency of alcohol and tobacco use. SPDEF was involved in the regulation of trans-genes linked to substance use.

    Conclusions: Taken together, the study findings describe a novel epigenetic mechanism that helps explain how psychosocial stress exposure influences adolescent substance abuse.

  • 76. Vukojević, Vladana
    et al.
    Gräslund, Astrid
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fluorescence imaging with single-molecule sensitivity and fluorescence correlation spectroscopy of cell-penetrating neuropeptides2011In: Neuropeptides, ISSN 0143-4179, E-ISSN 1532-2785, Vol. 789, p. 147-170Article in journal (Refereed)
    Abstract [en]

    Neuropeptide-plasma membrane interactions in the absence of a corresponding specific receptor may result in neuropeptide translocation into the cell. Translocation across the plasma membrane may represent a previously unknown mechanism by which neuropeptides can signal information to the cell interior. We introduce here two complementary optical methods with single-molecule sensitivity, fluorescence imaging with avalanche photodiode detectors (APD imaging) and fluorescence correlation spectroscopy (FCS), and demonstrate how they may be applied for the analysis of neuropeptide ability to penetrate into live cells in real time. APD imaging enables us to visualize fluorescently labeled neuropeptide molecules at very low, physiologically relevant concentrations, whereas FCS enables us to characterize quantitatively their concentration and diffusion properties in different cellular compartments. Application of these methodologies for the analysis of the endogenous opioid peptide dynorphin A (Dyn A), a ligand for the kappa-opioid receptor (KOP), demonstrated that this neuropeptide may translocate across the plasma membrane of living cells and enter the cellular interior without binding to its cognate receptor.

  • 77. Walker, Brendan M.
    et al.
    Valdez, Glenn R.
    McLaughlin, Jay P.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Targeting dynorphin/kappa opioid receptor systems to treat alcohol abuse and dependence2012In: Alcohol, ISSN 0741-8329, E-ISSN 1873-6823, Vol. 46, no 4, p. 359-370Article in journal (Refereed)
    Abstract [en]

    This review represents the focus of a symposium that was presented at the "Alcoholism and Stress: A Framework for Future Treatment Strategies" conference in Volterra, Italy on May 3-6, 2011 and organized/chaired by Dr. Brendan M. Walker. The primary goal of the symposium was to evaluate and disseminate contemporary findings regarding the emerging role of kappa-opioid receptors (KORs) and their endogenous ligands dynorphins (DYNs) in the regulation of,escalated alcohol consumption, negative affect and cognitive dysfunction associated with alcohol dependence, as well as DYN/KOR mediation of the effects of chronic stress on alcohol reward and seeking behaviors. Dr. Glenn Valdez described a role for KORs in the anxiogenic effects of alcohol withdrawal. Dr. Jay McLaughlin focused on the role of KORs in repeated stress-induced potentiation of alcohol reward and increased alcohol consumption. Dr. Brendan Walker presented data characterizing the effects of KOR antagonism within the extended amygdala on withdrawal-induced escalation of alcohol self-administration in dependent animals. Dr. Georgy Bakalkin concluded with data indicative of altered DYNs and KORs in the prefrontal cortex of alcohol dependent humans that could underlie diminished cognitive performance. Collectively, the data presented within this symposium identified the multifaceted contribution of KORs to the characteristics of acute and chronic alcohol-induced behavioral dysregulation and provided a foundation for the development of pharmacotherapeutic strategies to treat certain aspects of alcohol use disorders.

  • 78.
    Watanabe, Hiroyuki
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fitting, Sylvia
    Hussain, Muhammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kononenko, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Iatsyshyna, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Yoshitake, Takashi
    Kehr, Jan
    Alkass, Kanar
    Druid, Henrik
    Wadensten, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Andren, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wedell, Douglas
    Krishtal, Oleg
    Hauser, Kurt
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karpyak, Victor
    Yakovleva, Tatjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Asymmetry of the Endogenous Opioid System in the Human Anterior Cingulate: a Putative Molecular Basis for Lateralization of Emotions and Pain2015In: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 25, no 1, p. 97-108Article in journal (Refereed)
    Abstract [en]

    Lateralization of processing of positive and negative emotions and pain suggests an asymmetric distribution of the neurotransmitter systems regulating these functions between the left and right brain hemispheres. By virtue of their ability to selectively mediate euphoria, dysphoria and pain, the m-, d- and k-opioid receptors and their endogenous ligands may subserve these lateralized functions. We addressed this hypothesis by comparing the levels of the opioid receptors and peptides in the left and right anterior cingulate cortex (ACC), a key area for emotion and pain processing. Opioid mRNAs and peptides and five “classical” neurotransmitters were analyzed in postmortem tissues from 20 human subjects. Leu-enkephalin-Arg and Met-enkephalin-Arg-Phe, preferential d-/m- and k-/m-opioid agonists demonstrated marked lateralization to the left and right ACC, respectively. Dynorphin B strongly correlated with Leu-enkephalin-Arg in the left but not right ACC suggesting different mechanisms of conversion of this k-opioid agonist to d-/m-opioid ligand in the two hemispheres; in the right ACC dynorphin B may be cleaved by PACE4, a proprotein convertase regulating left-right asymmetry formation. These findings suggest that region-specific lateralization of neuronal networks expressing opioid peptides underlyes in part lateralization of higher functions including positive and negative emotions and pain in the human brain.

  • 79.
    Watanabe, Hiroyuki
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Henriksson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ohnishi, Yoshinori N.
    Department of Neuroscience, Mount Sinai School of Medicine, New York, USA.
    Ohnishi, Yoko H.
    Department of Neuroscience, Mount Sinai School of Medicine, New York, USA.
    Harper, Clive
    Discipline of Pathology, University of Sydney, Sydney, Australia.
    Sheedy, Donna
    Discipline of Pathology, University of Sydney, Sydney, Australia.
    Garrick, Therese
    Discipline of Pathology, University of Sydney, Sydney, Australia.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nestler, Eric J.
    Department of Neuroscience, Mount Sinai School of Medicine, New York, USA.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Yakovleva, Tatjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    FOSB proteins in the orbitofrontal and dorsolateral prefrontal cortices of human alcoholics2009In: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 14, no 3, p. 294-297Article in journal (Refereed)
    Abstract [en]

    The transcription factor DeltaFosB is accumulated in the addiction circuitry, including the orbitofrontal and medial prefrontal cortices of rodents chronically exposed to ethanol or other drugs of abuse, and has been suggested to play a direct role in addiction maintenance. To address this hypothesis in the context of substance dependence in humans, we compared the immunoreactivities of FOSB proteins in the orbitofrontal and dorsolateral prefrontal cortices (OFC and DLPFC respectively) between controls and alcoholics using semiquantitative immunoblotting. In both structures, we detected three forms of FOSB, one of which was DeltaFOSB, but in neither case did their immunoreactivities differ between the groups. Our results indicate that the DeltaFOSB immunoreactivity in the human brain is very low, and that it is not accumulated in the OFC and DLPFC of human alcoholics, suggesting that it may not be directly involved in addiction maintenance, at least not in ethanol dependence.

  • 80.
    Watanabe, Hiroyuki
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mizoguchi, Hirokazu
    Verbeek, Dineke S.
    Kuzmin, Alexander
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Krishtal, Oleg
    Sakurada, Shinobu
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Non-opioid nociceptive activity of human dynorphin mutants that cause neurodegenerative disorder spinocerebellar ataxia type 232012In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 35, no 2, p. 306-310Article in journal (Refereed)
    Abstract [en]

    We previously identified four missense mutations in the prodynorphin gene that cause human neurodegenerative disorder spinocerebellar ataxia type 23 (SCA23). Three mutations substitute Leu(5), Arg(6), and Arg(9) to Ser (L5S), Trp (R6W) and Cys (R9C) in dynorphin A(1-17) (Dyn A), a peptide with both opioid activities and non-opioid neurodegenerative actions. It has been reported that Dyn A administered intrathecally (i.t.) in femtomolar doses into mice produces nociceptive behaviors consisting of hindlimb scratching along with biting and licking of the hindpaw and tail (SBL responses) through a non-opioid mechanism. We here evaluated the potential of the three mutant peptides to produce similar behaviors. Compared to the wild type (WT)-peptide, the relative potency of Dyn A R6W, L5S and R9C peptides for SBL responses was 50-, 33- and 2-fold higher, and Dyn A R6W and L5S induced the SBL responses at a 10-30-fold lower doses. Dyn A R6W was the most potent peptide. The SBL responses induced by Dyn A R6W were dose dependently inhibited by morphine (i.p.; 0.1-1 mg/kg) or MK-801, an NMDA ion channel blocker (i.t. co-administration; 5-7.5 nmol). CP-99,994, a tachykinin NK1 receptor antagonist (i.t. co-administration; 2 nmol) and naloxone (i.p.; 5 mg/kg) failed to block effects of Dyn A R6W. Thus, similarly to Dyn A WT, the SBL responses induced by Dyn A R6W may involve the NMDA receptor but are not mediated through the opioid and tachykinin NK1 receptors. Enhanced non-opioid excitatory activities of Dyn A mutants may underlie in part development of SCA23.

  • 81.
    Watanabe, Hiroyuki
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Zhang, Mengliang
    Lund Univ, Dept Expt Med Sci, Neuronano Res Ctr, Lund, Sweden.
    Sarkisyan, Daniil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kononenko, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Clausen, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Iakovleva, Tatiana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Asymmetric Hindlimb Motor Response To Focal Traumatic Brain Injury Is Controlled By Side-Specific Opioid Mechanism2018In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 35, no 16, p. A79-A79Article in journal (Other academic)
  • 82.
    Winham, Stacey J.
    et al.
    Mayo Clin, Hlth Sci Res, Rochester, MN USA..
    Preuss, Ulrich W.
    Univ Halle Wittenberg, Dept Psychiat Psychotherapy & Psychosomat, D-06108 Halle, Germany..
    Geske, Jennifer R.
    Mayo Clin, Hlth Sci Res, Rochester, MN USA..
    Zill, Peter
    Ludwig Maximilians Univ Munchen, Dept Psychiat, Sect Psychiat Genet & Neurochem, Munich, Germany..
    Heit, John A.
    Mayo Clin, Div Cardiovasc Dis, Rochester, MN USA..
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Biernacka, Joanna M.
    Mayo Clin, Hlth Sci Res, Rochester, MN USA.;Mayo Clin, Psychiat & Psychol, Rochester, MN 55902 USA..
    Karpyak, Victor M.
    Mayo Clin, Psychiat & Psychol, Rochester, MN 55902 USA..
    Associations of prodynorphin sequence variation with alcohol dependence and related traits are phenotype-specific and sex-dependent2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 15670Article in journal (Refereed)
    Abstract [en]

    We previously demonstrated that prodynorphin (PDYN) haplotypes and single nucleotide polymorphism (SNP) rs2281285 are associated with alcohol dependence and the propensity to drink in negative emotional states, and recent studies suggest that PDYN gene effects on substance dependence risk may be sex-related. We examined sex-dependent associations of PDYN variation with alcohol dependence and related phenotypes, including negative craving, time until relapse after treatment and the length of sobriety episodes before seeking treatment, in discovery and validation cohorts of European ancestry. We found a significant haplotype-by-sex interaction (p = 0.03), suggesting association with alcohol dependence in males (p = 1E-4) but not females. The rs2281285G allele increased risk for alcohol dependence in males in the discovery cohort (OR = 1.49, p = 0.002), with a similar trend in the validation cohort (OR = 1.35, p = 0.086). However, rs2281285 showed a trend towards association with increased negative craving in females in both the discovery (beta = 10.16, p = 0.045) and validation samples (OR = 7.11, p = 0.066). In the discovery cohort, rs2281285 was associated with time until relapse after treatment in females (HR = 1.72, p = 0.037); in the validation cohort, it was associated with increased length of sobriety episodes before treatment in males (beta = 13.49, p = 0.001). Our findings suggest that sex-dependent effects of PDYN variants in alcohol dependence are phenotype-specific.

  • 83. Winham, Stacey J.
    et al.
    Preuss, Ulrich W.
    Geske, Jennifer R.
    Zill, Peter
    Heit, John A.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Biernacka, Joanna M.
    Karpyak, Victor M.
    Sex-Specific Association of Prodynorphin Sequence Variation with Alcohol Dependence and Related Phenotypes2015In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 77, no 9, p. 408S-408S, article id 1115Article in journal (Other academic)
  • 84.
    Yakovleva, Tatjana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bazov, Igor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Watanabe, Hiroyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hauser, Kurt
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Transcriptional control of maladaptive and protective responses in alcoholics: a role of the NF-κB system2010In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 25, no Suppl. 1, p. S29-S38Article, review/survey (Refereed)
    Abstract [en]

    Alcohol dependence and associated cognitive impairment appear to result from maladaptive neuroplasticity in response to chronic alcohol consumption, neuroinflammation and neurodegeneration. The inherent stability of behavioral alterations associated with the addicted state suggests that transcriptional and epigenetic mechanisms are operative. NF-κB transcription factors are regulators of synaptic plasticity and inflammation, and responsive to a variety of stimuli including alcohol. These factors are abundant in the brain where they have diverse functions that depend on the composition of the NF-κB complex and cellular context. In neuron cell bodies, NF-κB is constitutively active, and involved in neuronal injury and neuroprotection. However, at the synapse, NF-κB is present in a latent form and upon activation is transported to the cell nucleus. In glia, NF-κB is inducible and regulates inflammatory processes that exacerbate alcohol-induced neurodegeneration. Animal studies demonstrate that acute alcohol exposure transiently activates NF-κB, which induces neuroinflammatory responses and neurodegeneration. Postmortem studies of brains of human alcoholics suggest that repeated cycles of alcohol consumption and withdrawal cause adaptive changes in the NF-κB system that may permit the system to better tolerate excessive stimulation. This type of tolerance, ensuring a low degree of responsiveness to applied stimuli, apparently differs from that in the immune system, and may represent a compensatory response that protects brain cells against alcohol neurotoxicity. This view is supported by findings showing preferential downregulation of pro-apoptotic gene expression in the affected brain areas in human alcoholics. Although further verification is needed, we speculate that NF-κB-driven neuroinflammation and disruption to neuroplasticity play a significant role in regulating alcohol dependence and cognitive impairment.

  • 85.
    Yakovleva, Tatjana
    et al.
    Department of Clinical Neuroscience, Karolinska Institute and Hospital, Stockholm, Sweden.
    Marinova, Z.
    Department of Clinical Neuroscience, Karolinska Institute and Hospital, Stockholm, Sweden.
    Kuzmin, A.
    Department of Clinical Neuroscience, Karolinska Institute and Hospital, Stockholm, Sweden.
    Seidah, N. G.
    Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Que., Canada.
    Haroutunian, V.
    Department of Psychiatry, The Mount Sinai School of Medicine, New York, USA.
    Terenius, L.
    Department of Clinical Neuroscience, Karolinska Institute and Hospital, Stockholm, Sweden.
    Bakalkin, G.
    Department of Clinical Neuroscience, Karolinska Institute and Hospital, Stockholm, Sweden.
    Dysregulation of dynorphins in Alzheimer disease2007In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 28, no 11, p. 1700-8Article in journal (Refereed)
    Abstract [en]

    The opioid peptides dynorphins may be involved in pathogenesis of Alzheimer disease (AD) by inducing neurodegeneration or cognitive impairment. To test this hypothesis, the dynorphin system was analyzed in postmortem samples from AD and control subjects, and subjects with Parkinson or cerebro-vascular diseases for comparison. Dynorphin A, dynorphin B and related neuropeptide nociceptin were determined in the Brodmann area 7 by radioimmunoassay. The precursor protein prodynorphin, processing convertase PC2 and the neuroendocrine pro7B2 and 7B2 proteins required for PC2 maturation were analyzed by Western blot. AD subjects displayed robustly elevated levels of dynorphin A and no differences in dynorphin B and nociceptin compared to controls. Subjects with Parkinson or cerebro-vascular diseases did not differ from controls with respect to any of the three peptides. PC2 levels were also increased, whereas, those of prodynorphin and pro7B2/7B2 were not changed in AD. Dynorphin A levels correlated with the neuritic plaque density. These results along with the known non-opioid ability of dynorphin A to induce neurodegeneration suggest a role for this neuropeptide in AD neuropathology.

  • 86.
    Yakovleva, Tatjana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Watanabe, Hiroyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala Univ, Uppsala, Sweden..
    Lateralized response in endogenous pathogenic peptides dynorphins caused by traumatic brain injury: Relevance for human psychopathology2016In: Brain Injury, ISSN 0269-9052, E-ISSN 1362-301X, Vol. 30, no 5-6, p. 733-733Article in journal (Other academic)
  • 87.
    Zhang, Mengliang
    et al.
    Lund Univ, Dept Expt Med Sci, Neuronano Res Ctr, Lund, Sweden.
    Watanabe, Hiroyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sarkisyan, Daniil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Thelin, Jonas
    Lund Univ, Dept Expt Med Sci, Neuronano Res Ctr, Lund, Sweden.
    Schouenborg, Jens
    Lund Univ, Dept Expt Med Sci, Neuronano Res Ctr, Lund, Sweden.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala Univ, Pharmaceut Biosci, Uppsala, Sweden.
    ASYMMETRIC HINDLIMB POSTURE AND WITHDRAW REFLEXES INDUCED BY UNILATERAL BRAIN INJURY ARE ENCODED IN SPINAL CORD2018In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 35, no 16, p. A208-A208Article in journal (Other academic)
  • 88.
    Ökvist, Anna
    et al.
    The Section of Alcohol and Drug Dependence Research, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Johansson, Sofia
    The Section of Alcohol and Drug Dependence Research, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Kuzmin, Alexander
    The Section of Alcohol and Drug Dependence Research, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Bazov, Igor
    The Section of Alcohol and Drug Dependence Research, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Merino-Martinez, Roxana
    Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
    Ponomarev, Igor
    Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, Texas, United States of America.
    Mayfield, R. Dayne
    Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, Texas, United States of America.
    Harris, R. Adron
    Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, Texas, United States of America.
    Sheedy, Donna
    Discipline of Pathology, University of Sydney, Sydney, New South Wales, Australia.
    Garrick, Therese
    Discipline of Pathology, University of Sydney, Sydney, New South Wales, Australia.
    Harper, Clive
    Discipline of Pathology, University of Sydney, Sydney, New South Wales, Australia.
    Hurd, Yasmin L.
    Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, United States of America and Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, New York, United States of America.
    Terenius, Lars
    The Section of Alcohol and Drug Dependence Research, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Ekström, Tomas J.
    The Section of Alcohol and Drug Dependence Research, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Yakovleva, Tatjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Neuroadaptations in human chronic alcoholics: dysregulation of the NF-κB system2007In: PLoS ONE, ISSN 1932-6203, Vol. 2, no 9, p. e930-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Alcohol dependence and associated cognitive impairments apparently result from neuroadaptations to chronic alcohol consumption involving changes in expression of multiple genes. Here we investigated whether transcription factors of Nuclear Factor-kappaB (NF-kappaB) family, controlling neuronal plasticity and neurodegeneration, are involved in these adaptations in human chronic alcoholics. METHODS AND FINDINGS: Analysis of DNA-binding of NF-kappaB (p65/p50 heterodimer) and the p50 homodimer as well as NF-kappaB proteins and mRNAs was performed in postmortem human brain samples from 15 chronic alcoholics and 15 control subjects. The prefrontal cortex involved in alcohol dependence and cognition was analyzed and the motor cortex was studied for comparison. The p50 homodimer was identified as dominant kappaB binding factor in analyzed tissues. NF-kappaB and p50 homodimer DNA-binding was downregulated, levels of p65 (RELA) mRNA were attenuated, and the stoichiometry of p65/p50 proteins and respective mRNAs was altered in the prefrontal cortex of alcoholics. Comparison of a number of p50 homodimer/NF-kappaB target DNA sites, kappaB elements in 479 genes, down- or upregulated in alcoholics demonstrated that genes with kappaB elements were generally upregulated in alcoholics. No significant differences between alcoholics and controls were observed in the motor cortex. CONCLUSIONS: We suggest that cycles of alcohol intoxication/withdrawal, which may initially activate NF-kappaB, when repeated over years downregulate RELA expression and NF-kappaB and p50 homodimer DNA-binding. Downregulation of the dominant p50 homodimer, a potent inhibitor of gene transcription apparently resulted in derepression of kappaB regulated genes. Alterations in expression of p50 homodimer/NF-kappaB regulated genes may contribute to neuroplastic adaptation underlying alcoholism.

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