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  • 1.
    Bakalkin, Georgy
    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.
    Hussain, Muhammad Zubair
    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.
    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.
    Karpyak, V.
    Yakovleva, Tatiana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Dysregulation of the endogenous opioid system in the brain of human alcoholics2013In: European psychiatry, ISSN 0924-9338, E-ISSN 1778-3585, Vol. 28, no S1, p. 2297-Article in journal (Other academic)
  • 2.
    Bakalkin, Georgy
    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.
    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.
    Stålhandske, Lada
    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.
    TBI induced spinal cord plasticity: The endogenous opioid system mediates trauma effects on motor reflexes2016In: Brain Injury, ISSN 0269-9052, E-ISSN 1362-301X, Vol. 30, no 5-6, p. 712-712Article in journal (Other academic)
  • 3.
    Bazov, Igor
    et al.
    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.
    Watanabe, Hiroyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kuntić, Vesna
    Sarkisyan, Daniil
    Taqi, Malik Mumtaz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hussain, Muhammad Zubair
    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.
    The endogenous opioid system in human alcoholics: molecular adaptations in brain areas involved in cognitive control of addiction2013In: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 18, no 1, p. 161-169Article in journal (Refereed)
    Abstract [en]

    The endogenous opioid system (EOS) plays a critical role in addictive processes. Molecular dysregulations in this system may be specific for different stages of addiction cycle and neurocircuitries involved and therefore may differentially contribute to the initiation and maintenance of addiction. Here we evaluated whether the EOS is altered in brain areas involved in cognitive control of addiction including the dorsolateral prefrontal cortex (dl-PFC), orbitofrontal cortex (OFC) and hippocampus in human alcohol-dependent subjects. Levels of EOS mRNAs were measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and levels of dynorphins by radioimmunoassay (RIA) in post-mortem specimens obtained from 14 alcoholics and 14 controls. Prodynorphin mRNA and dynorphins in dl-PFC, κ-opioid receptor mRNA in OFC and dynorphins in hippocampus were up-regulated in alcoholics. No significant changes in expression of proenkephalin, and µ- and δ-opioid receptors were evident; pro-opiomelanocortin mRNA levels were below the detection limit. Activation of the κ-opioid receptor by up-regulated dynorphins in alcoholics may underlie in part neurocognitive dysfunctions relevant for addiction and disrupted inhibitory control.

  • 4.
    Bazov, Igor
    et al.
    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.
    Kononenko, Olga
    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.
    Karpyak, Victor M.
    Mayo Clin, Coll Med, Dept Psychiat & Psychol, Rochester, MN 55905 USA.
    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 neuronal opioid gene expression concomitantly with neuronal decline in dorsolateral prefrontal cortex of human alcoholics2018In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 8, article id 122Article in journal (Refereed)
    Abstract [en]

    Molecular changes in cortical areas of addicted brain may underlie cognitive impairment and loss of control over intake of addictive substances and alcohol. Prodynorphin (PDYN) gives rise to dynorphin (DYNs) opioid peptides which target kappa-opioid receptor (KOR). DYNs mediate alcohol-induced impairment of learning and memory, while KOR antagonists block excessive, compulsive-like drug and alcohol self-administration in animal models. In human brain, the DYN/KOR system may undergo adaptive changes, which along with neuronal loss, may contribute to alcohol-associated cognitive deficit. We addressed this hypothesis by comparing the expression levels and co-expression (transcriptionally coordinated) patterns of PDYN and KOR (OPRK1) genes in dorsolateral prefrontal cortex (dlPFC) between human alcoholics and controls. Postmortem brain specimens of 53 alcoholics and 55 controls were analyzed. PDYN was found to be downregulated in dlPFC of alcoholics, while OPRK1 transcription was not altered. PDYN downregulation was confined to subgroup of subjects carrying C, a high-risk allele of PDYN promoter SNP rs1997794 associated with alcoholism. Changes in PDYN expression did not depend on the decline in neuronal proportion in alcoholics, and thereby may be attributed to transcriptional adaptations in alcoholic brain. Absolute expression levels of PDYN were lower compared to those of OPRK1, suggesting that PDYN expression is a limiting factor in the DYN/KOR signaling, and that the PDYN downregulation diminishes efficacy of DYN/KOR signaling in dlPFC of human alcoholics. The overall outcome of the DYN/KOR downregulation may be disinhibition of neurotransmission, which when overactivated could contribute to formation of alcohol-related behavior.

  • 5.
    Bazov, Igor
    et al.
    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.
    Kononenko, Olga
    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.
    Taqi, Malik Mumtaz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Faculty of Medicine, NORMENT, University of Oslo, Oslo, Norway.
    Stålhandske, Lada
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Verbeek, Dineke S
    Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.
    Mulder, Jan
    Department of Neuroscience, Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden.
    Rajkowska, Grazyna
    Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, USA.
    Sheedy, Donna
    Discipline of Pathology, Sydney Medical School, University of Sydney, Sydney NSW, Australia.
    Kril, Jillian
    Discipline of Pathology, Sydney Medical School, University of Sydney, Sydney NSW, Australia.
    Sun, Xueguang
    Zymo Research Corporation, 17062 Murphy Avenue, Irvine, CA, USA; Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA.
    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.
    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.
    Neuronal Expression of Opioid Gene is Controlled by Dual Epigenetic and Transcriptional Mechanism in Human Brain2018In: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 28, no 9, p. 3129-3142Article in journal (Refereed)
    Abstract [en]

    Molecular mechanisms that define patterns of neuropeptide expression are essential for the formation and rewiring of neural circuits. The prodynorphin gene (PDYN) gives rise to dynorphin opioid peptides mediating depression and substance dependence. We here demonstrated that PDYN is expressed in neurons in human dorsolateral prefrontal cortex (dlPFC), and identified neuronal differentially methylated region in PDYN locus framed by CCCTC-binding factor binding sites. A short, nucleosome size human-specific promoter CpG island (CGI), a core of this region may serve as a regulatory module, which is hypomethylated in neurons, enriched in 5-hydroxymethylcytosine, and targeted by USF2, a methylation-sensitive E-box transcription factor (TF). USF2 activates PDYN transcription in model systems, and binds to nonmethylated CGI in dlPFC. USF2 and PDYN expression is correlated, and USF2 and PDYN proteins are co-localized in dlPFC. Segregation of activatory TF and repressive CGI methylation may ensure contrasting PDYN expression in neurons and glia in human brain.

  • 6.
    Bazov, Igor
    et al.
    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.
    Kononenko, Olga
    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.
    Yakovleva, Tatiana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hansson, Anita C
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Inst Psychopharmacol, D-68159 Mannheim, Germany.
    Sommer, Wolfgang H
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Inst Psychopharmacol, D-68159 Mannheim, Germany.
    Spanagel, Rainer
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Inst Psychopharmacol, D-68159 Mannheim, Germany.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Dynorphin and κ-Opioid Receptor Dysregulation in the Dopaminergic Reward System of Human Alcoholics.2018In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 55, no 8, p. 7049-7061Article in journal (Refereed)
    Abstract [en]

    Molecular changes induced by excessive alcohol consumption may underlie formation of dysphoric state during acute and protracted alcohol withdrawal which leads to craving and relapse. A main molecular addiction hypothesis is that the upregulation of the dynorphin (DYN)/κ-opioid receptor (KOR) system in the nucleus accumbens (NAc) of alcohol-dependent individuals causes the imbalance in activity of D1- and D2 dopamine receptor (DR) expressing neural circuits that results in dysphoria. We here analyzed post-mortem NAc samples of human alcoholics to assess changes in prodynorphin (PDYN) and KOR (OPRK1) gene expression and co-expression (transcriptionally coordinated) patterns. To address alterations in D1- and D2-receptor circuits, we studied the regulatory interactions between these pathways and the DYN/KOR system. No significant differences in PDYN and OPRK1 gene expression levels between alcoholics and controls were evident. However, PDYN and OPRK1 showed transcriptionally coordinated pattern that was significantly different between alcoholics and controls. A downregulation of DRD1 but not DRD2 expression was seen in alcoholics. Expression of DRD1 and DRD2 strongly correlated with that of PDYN and OPRK1 suggesting high levels of transcriptional coordination between these gene clusters. The differences in expression and co-expression patterns were not due to the decline in neuronal proportion in alcoholic brain and thereby represent transcriptional phenomena. Dysregulation of DYN/KOR system and dopamine signaling through both alterations in co-expression patterns of opioid genes and decreased DRD1 gene expression may contribute to imbalance in the activity of D1- and D2-containing pathways which may lead to the negative affective state in human alcoholics.

  • 7.
    Duarte, Joana
    et al.
    Univ Porto, Inst Invest & Inovacao Saude, Porto, Portugal;Univ Porto, Neuronal Networks Grp, IBMC, Rua Alfredo Allen 208, P-4200135 Porto, Portugal.
    Fernandes, Elisabete C.
    Univ Porto, Inst Invest & Inovacao Saude, Porto, Portugal;Univ Porto, Neuronal Networks Grp, IBMC, Rua Alfredo Allen 208, P-4200135 Porto, Portugal.
    Kononenko, Olga
    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.
    Luz, Liliana L.
    Univ Porto, Inst Invest & Inovacao Saude, Porto, Portugal;Univ Porto, Neuronal Networks Grp, IBMC, Rua Alfredo Allen 208, P-4200135 Porto, Portugal.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Safronov, Boris V.
    Univ Porto, Inst Invest & Inovacao Saude, Porto, Portugal;Univ Porto, Neuronal Networks Grp, IBMC, Rua Alfredo Allen 208, P-4200135 Porto, Portugal.
    Differential suppression of the ipsi- and contralateral nociceptive reflexes in the neonatal rat spinal cord by agonists of μ-, δ- and κ-opioid receptors2019In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1717, p. 182-189Article in journal (Refereed)
    Abstract [en]

    Nociceptive discharges caused by the unilateral tissue damage are processed in the spinal cord by both ipsi- and contralateral neuronal circuits. The mechanisms of the neurotransmitter control of this bilateral excitation spread is poorly understood. Spinally administered opiates are known to suppress nociceptive transmission and nociceptive withdrawal reflexes. Here we investigated whether three major types of opioid receptors are involved in the bilateral control of the spinal nociceptive sensorimotor processing. Effects of the μ-, δ- and κ-opioid receptor agonists on the ipsi- and contralateral nociceptive reflexes were studied by recording slow ventral root potentials in an isolated spinal cord preparation of the new-born rat. Absolute levels of expression of the opioid genes were analyzed by the droplet digital PCR. Ipsi- and contralateral slow ventral root potentials were most strongly suppressed by the μ-opioid receptor agonist DAMGO, by 63% and 85%, followed by the κ-opioid receptor agonist U-50488H, by 44% and 73%, and δ-opioid receptor agonist leucine-enkephalin, by 27% and 49%, respectively. All these agonists suppressed stronger contra- than ipsilateral responses. Naloxone prevented effects of the agonists indicating that they act through opioid receptors, which, as we show, are expressed in the neonatal spinal cord at the levels similar to those in adults. Thus, opioid receptor agonists suppress the segmental nociceptive reflexes. Stronger contralateral effects suggest that the endogenous opioid system regulates sensorimotor processing in the spinal commissural pathways. These effects of opioids may be relevant for treatment of symmetric clinical pain symptoms caused by unilateral tissue injury.

  • 8.
    Jin, Zhe
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bazov, Igor
    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.
    Korpi, Esa R
    Univ Helsinki, Inst Biomed, FIN-00014 Helsinki, Finland.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Selective Changes of GABA(A) Channel Subunit mRNAs in the Hippocampus and Orbitofrontal Cortex but not in Prefrontal Cortex of Human Alcoholics2012In: Frontiers in Cellular Neuroscience, ISSN 1662-5102, E-ISSN 1662-5102, Vol. 5, article id 30Article in journal (Refereed)
    Abstract [en]

    Alcohol dependence is a common chronic relapsing disorder. The development of alcohol dependence has been associated with changes in brain GABA(A) channel-mediated neurotransmission and plasticity. We have examined mRNA expression of the GABA(A) channel subunit genes in three brain regions in individuals with or without alcohol dependence using quantitative real-time PCR assay. The levels of selective GABA(A) channel subunit mRNAs were altered in specific brain regions in alcoholic subjects. Significant increase in the α1, α4, α5, β1, and γ1 subunit mRNAs in the hippocampal dentate gyrus region, and decrease in the β2 and δ subunit mRNAs in the orbitofrontal cortex were identified whereas no changes in the dorsolateral prefrontal cortex were detected. The data increase our understanding of the role of GABA(A) channels in the development of alcohol dependence.

  • 9.
    Jin, Zhe
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bhandage, Amol K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bazov, Igor
    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.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Korpi, Esa R.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Expression of specific ionotropic glutamate and GABA-A receptor subunits is decreased in central amygdala of alcoholics2014In: Frontiers in Cellular Neuroscience, ISSN 1662-5102, E-ISSN 1662-5102, Vol. 8, p. 288-Article in journal (Refereed)
    Abstract [en]

    The central amygdala (CeA) has a role for mediating fear and anxiety responses. It is also involved in emotional imbalance caused by alcohol abuse and dependence and in regulating relapse to alcohol abuse. Growing evidences suggest that excitatory glutamatergic and inhibitory gamma-aminobutyric acid-ergic (GABAergic) transmissions in the CeA are affected by chronic alcohol exposure. Human post-mortem CeA samples from male alcoholics (n = 9) and matched controls (n = 9) were assayed for the expression level of ionotropic glutamate and GABA-A receptors subunit mRNAs using quantitative real-time reverse transcription-PCB (RT-qPCR). Our data revealed that out of the 16 ionotropic glutamate receptor subunits, mRNAs encoding two AMPA P-amino-3-(3-hydroxy-5-methyl-isoxazol-4-y1)propanoic acid] receptor subunits GluA1 and GluA4; one kainate receptor subunit GluK2; one NMDA (N-methyl-D-aspartate) receptor subunit GluN2D and one delta receptor subunit GluD2 were significantly decreased in the CeA of alcoholics. In contrast, of the 19 GABA-A receptor subunits, only the mRNA encoding the a2 subunit was significantly down-regulated in the CeA of the alcoholics as compared with control subjects. Our findings imply that the down-regulation of specific ionotropic glutamate and GABA-A receptor subunits in the CeA of alcoholics may represent one of the molecular substrates underlying the new balance between excitatory and inhibitory neurotransmission in alcohol dependence.

  • 10.
    Jin, Zhe
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bhandage, Amol K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bazov, Igor
    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.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Korpi, Esa R
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Selective increases of AMPA, NMDA, and kainate receptor subunit mRNAs in the hippocampus and orbitofrontal cortex but not in prefrontal cortex of human alcoholics2014In: Frontiers in Cellular Neuroscience, ISSN 1662-5102, E-ISSN 1662-5102, Vol. 8, p. 11-Article in journal (Refereed)
    Abstract [en]

    Glutamate is the main excitatory transmitter in the human brain. Drugs that affect the glutamatergic signaling will alter neuronal excitability. Ethanol inhibits glutamate receptors. We examined the expression level of glutamate receptor subunit mRNAs in human post-mortem samples from alcoholics and compared the results to brain samples from control subjects. RNA from hippocampal dentate gyrus (HP-DG), orbitofrontal cortex (OFC), and dorso-lateral prefrontal cortex (DL-PFC) samples from 21 controls and 19 individuals with chronic alcohol dependence were included in the study. Total RNA was assayed using quantitative RT-PCR. Out of the 16 glutamate receptor subunits, mRNAs encoding two AMPA [2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid] receptor subunits GluA2 and GluA3; three kainate receptor subunits GluK2, GluK3 and GluK5 and five NMDA (N-methyl-D-aspartate) receptor subunits GluN1, GluN2A, GluN2C, GluN2D, and GluN3A were significantly increased in the HP-DG region in alcoholics. In the OFC, mRNA encoding the NMDA receptor subunit GluN3A was increased, whereas in the DL-PFC, no differences in mRNA levels were observed. Our laboratory has previously shown that the expression of genes encoding inhibitory GABA-A receptors is altered in the HP-DG and OFC of alcoholics (Jin et al., 2011). Whether the changes in one neurotransmitter system drives changes in the other or if they change independently is currently not known. The results demonstrate that excessive long-term alcohol consumption is associated with altered expression of genes encoding glutamate receptors in a brain region-specific manner. It is an intriguing possibility that genetic predisposition to alcoholism may contribute to these gene expression changes.

  • 11.
    Karpyak, V.
    et al.
    Uppsala University. Mayo Clin, Rochester, MN USA.;Karolinska Inst, Stockholm, Sweden.;Cent Inst Mental Hlth, Mannheim, Germany.;Univ Bonn, Bonn, Germany..
    Biernacka, J.
    Uppsala University. Mayo Clin, Rochester, MN USA.;Karolinska Inst, Stockholm, Sweden.;Cent Inst Mental Hlth, Mannheim, Germany.;Univ Bonn, Bonn, Germany..
    Geske, J.
    Uppsala University. Mayo Clin, Rochester, MN USA.;Karolinska Inst, Stockholm, Sweden.;Cent Inst Mental Hlth, Mannheim, Germany.;Univ Bonn, Bonn, Germany..
    Jenkins, G.
    Uppsala University. Mayo Clin, Rochester, MN USA.;Karolinska Inst, Stockholm, Sweden.;Cent Inst Mental Hlth, Mannheim, Germany.;Univ Bonn, Bonn, Germany..
    Cunningham, Janet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital. Mayo Clin, Rochester, MN USA.;Karolinska Inst, Stockholm, Sweden.;Cent Inst Mental Hlth, Mannheim, Germany.;Univ Bonn, Bonn, Germany..
    Rueegg, J.
    Uppsala University. Mayo Clin, Rochester, MN USA.;Karolinska Inst, Stockholm, Sweden.;Cent Inst Mental Hlth, Mannheim, Germany.;Univ Bonn, Bonn, Germany..
    Kononenko, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Mayo Clin, Rochester, MN USA.;Karolinska Inst, Stockholm, Sweden.;Cent Inst Mental Hlth, Mannheim, Germany.;Univ Bonn, Bonn, Germany..
    Abulseoud, O.
    Uppsala University. Mayo Clin, Rochester, MN USA.;Karolinska Inst, Stockholm, Sweden.;Cent Inst Mental Hlth, Mannheim, Germany.;Univ Bonn, Bonn, Germany..
    Hall-Flavin, D.
    Uppsala University. Mayo Clin, Rochester, MN USA.;Karolinska Inst, Stockholm, Sweden.;Uppsala Univ, Uppsala, Sweden.;Cent Inst Mental Hlth, Mannheim, Germany.;Univ Bonn, Bonn, Germany..
    Loukianova, L.
    Uppsala University. Mayo Clin, Rochester, MN USA.;Karolinska Inst, Stockholm, Sweden;Cent Inst Mental Hlth, Mannheim, Germany.;Univ Bonn, Bonn, Germany..
    Schneekloth, T.
    Uppsala University. Mayo Clin, Rochester, MN USA.;Karolinska Inst, Stockholm, Sweden.;Cent Inst Mental Hlth, Mannheim, Germany.;Univ Bonn, Bonn, Germany..
    Frank, J.
    Uppsala University. Mayo Clin, Rochester, MN USA.;Karolinska Inst, Stockholm, Sweden.;Cent Inst Mental Hlth, Mannheim, Germany.;Univ Bonn, Bonn, Germany..
    Noethen, M.
    Uppsala University. Mayo Clin, Rochester, MN USA.;Karolinska Inst, Stockholm, Sweden.;Cent Inst Mental Hlth, Mannheim, Germany.;Univ Bonn, Bonn, Germany..
    Rietschel, M.
    Uppsala University. Mayo Clin, Rochester, MN USA.;Karolinska Inst, Stockholm, Sweden.;Cent Inst Mental Hlth, Mannheim, Germany.;Univ Bonn, Bonn, Germany..
    Kiefer, F.
    Uppsala University. Mayo Clin, Rochester, MN USA.;Karolinska Inst, Stockholm, Sweden.;Cent Inst Mental Hlth, Mannheim, Germany.;Univ Bonn, Bonn, Germany..
    Mann, K.
    Uppsala University. Mayo Clin, Rochester, MN USA.;Karolinska Inst, Stockholm, Sweden.;Cent Inst Mental Hlth, Mannheim, Germany.;Univ Bonn, Bonn, Germany..
    Weinshilboum, R.
    Uppsala University. Mayo Clin, Rochester, MN USA.;Karolinska Inst, Stockholm, Sweden.;Cent Inst Mental Hlth, Mannheim, Germany.;Univ Bonn, Bonn, Germany..
    Frye, Maike
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Mayo Clin, Rochester, MN USA.;Karolinska Inst, Stockholm, Sweden.;Cent Inst Mental Hlth, Mannheim, Germany.;Univ Bonn, Bonn, Germany..
    Choi, D.
    Uppsala University. Mayo Clin, Rochester, MN USA.;Karolinska Inst, Stockholm, Sweden.;Cent Inst Mental Hlth, Mannheim, Germany.;Univ Bonn, Bonn, Germany..
    CLINICAL AND GENETIC MARKERS ASSOCIATED WITH THE LENGTH OF SOBRIETY IN HUMAN ALCOHOLICS TREATED WITH ACAMPROSATE2015In: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 39, p. 295A-295AArticle in journal (Other academic)
  • 12. Karpyak, V. M.
    et al.
    Biernacka, J. M.
    Geske, J. R.
    Jenkins, G. D.
    Cunningham, J. M.
    Rueegg, J.
    Kononenko, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Leontovich, A. A.
    Abulseoud, O. A.
    Hall-Flavin, D. K.
    Loukianova, L. L.
    Schneekloth, T. D.
    Skime, M. K.
    Frank, J.
    Noethen, M. M.
    Rietschel, M.
    Kiefer, F.
    Mann, K. F.
    Weinshilboum, R. M.
    Frye, M. A.
    Choi, D. S.
    Genetic markers associated with abstinence length in alcohol-dependent subjects treated with acamprosate2014In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 4, p. e462-Article in journal (Refereed)
    Abstract [en]

    Acamprosate supports abstinence in some alcohol-dependent subjects, yet predictors of response are unknown. To identify response biomarkers, we investigated associations of abstinence length with polymorphisms in candidate genes in glycine and glutamate neurotransmission pathways and genes previously implicated in acamprosate response. Association analyses were conducted in the discovery sample of 225 alcohol-dependent subjects treated with acamprosate for 3 months in community-based treatment programs in the United States. Data from 110 alcohol-dependent males treated with acamprosate in the study PREDICT were used for replication of the top association findings. Statistical models were adjusted for relevant covariates, including recruitment site and baseline clinical variables associated with response. In the discovery sample, shorter abstinence was associated with increased intensity of alcohol craving and lower number of days between the last drink and initiation of acamprosate treatment. After adjustment for covariates, length of abstinence was associated with the GRIN2B rs2058878 (P = 4.6 x 10(-5)). In the replication sample, shorter abstinence was associated with increased craving, increased depressive mood score and higher alcohol consumption. Association of abstinence length with GRIN2B rs2058878 was marginally significant (P = 0.0675); as in the discovery sample, the minor A allele was associated with longer abstinence. Furthermore, rs2300272, which is in strong linkage disequilibrium with rs2058878, was also associated with abstinence length (P = 0.049). This is the first report of a replicated association of genetic markers with the length of abstinence in acamprosate-treated alcoholics. Investigation of the underlying mechanisms of this association and its usefulness for individualized treatment selection should follow.

  • 13.
    Kononenko, Olga
    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.
    Gerashchenko, Ganna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Dyachok, Oleg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Verbeek, Dineke S
    Alkass, Kanar
    Druid, Henrik
    Andersson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mulder, Jan
    Svenningsen, Åsa Fex
    Rajkowska, Grazyna
    Stockmeier, Craig A
    Krishtal, Oleg
    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.
    Opioid precursor protein isoform is targeted to the cell nuclei in the human brain2017In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1861, no 2, p. 246-255Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Neuropeptide precursors are traditionally viewed as proteins giving rise to small neuropeptide molecules. Prodynorphin (PDYN) is the precursor protein to dynorphins, endogenous ligands for the κ-opioid receptor. Alternative mRNA splicing of neuropeptide genes may regulate cell- and tissue-specific neuropeptide expression and produce novel protein isoforms. We here searched for novel PDYN mRNA and their protein product in the human brain.

    METHODS: Novel PDYN transcripts were identified using nested PCR amplification of oligo(dT) selected full-length capped mRNA. Gene expression was analyzed by qRT-PCR, PDYN protein by western blotting and confocal imaging, dynorphin peptides by radioimmunoassay. Neuronal nuclei were isolated using fluorescence-activated nuclei sorting (FANS) from postmortem human striatal tissue. Immunofluorescence staining and confocal microscopy was performed for human caudate nucleus.

    RESULTS: Two novel human PDYN mRNA splicing variants were identified. Expression of one of them was confined to the striatum where its levels constituted up to 30% of total PDYN mRNA. This transcript may be translated into ∆SP-PDYN protein lacking 13 N-terminal amino acids, a fragment of signal peptide (SP). ∆SP-PDYN was not processed to mature dynorphins and surprisingly, was targeted to the cell nuclei in a model cellular system. The endogenous PDYN protein was identified in the cell nuclei in human striatum by western blotting of isolated neuronal nuclei, and by confocal imaging.

    CONCLUSIONS AND GENERAL SIGNIFICANCE: High levels of alternatively spliced ∆SP-PDYN mRNA and nuclear localization of PDYN protein suggests a nuclear function for this isoform of the opioid peptide precursor in human striatum.

  • 14.
    Kononenko, Olga
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Key State Laboratory, Bogomoletz Institute of Physiology, Kiev, Ukraine.
    Galatenko, Vladimir
    Moscow State University.
    Andersson, Malin
    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.
    Zhou, Xingwu
    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. Department of Human Genetics, Institute of Molecular Biology and Genetics, Kiev, Ukraine.
    Mityakina, Irina
    Moscow State University.
    Yakovleva, Tatiana
    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.
    Ponomarev, Igor
    University of Texas.
    Krishtal, Oleg
    Bogomoletz Institute of Physiology, Kiev..
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Tonevitsky, Alex
    Moscow State University.
    Adkins, DeAnna L.
    Medical University of South Carolina.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Intra- and interregional coregulation of opioid genes: broken symmetry in spinal circuits2017In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 31, no 5, p. 1953-1963Article in journal (Refereed)
    Abstract [en]

    Regulation of the formation and rewiring of neural circuits by neuropeptides may require coordinated production of these signaling molecules and their receptors that may be established at the transcriptional level. Here, we address this hypothesis by comparing absolute expression levels of opioid peptides with their receptors, the largest neuropeptide family, and by characterizing coexpression (transcriptionally coordinated) patterns of these genes. We demonstrated that expression patterns of opioid genes highly correlate within and across functionally and anatomically different areas. Opioid peptide genes, compared with their receptor genes, are transcribed at much greater absolute levels, which suggests formation of a neuropeptide cloud that covers the receptor-expressed circuits. Surprisingly, we found that both expression levels and the proportion of opioid receptors are strongly lateralized in the spinal cord, interregional coexpression patterns are side specific, and intraregional coexpression profiles are affected differently by left-and right-side unilateral body injury. We propose that opioid genes are regulated as interconnected components of the same molecular system distributed between distinct anatomic regions. The striking feature of this system is its asymmetric coexpression patterns, which suggest side-specific regulation of selective neural circuits by opioid neurohormones.

  • 15.
    Kononenko, Olga
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mityakina, Irina
    Moscow MV Lomonosov State Univ, Moscow, Russia..
    Galatenko, Vladimir
    Moscow MV Lomonosov State Univ, Moscow, Russia.;Univ Haifa, Tauber Bioinformat Res Ctr, Haifa, Israel..
    Watanabe, Hiroyuki
    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.
    Gerashchenko, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Inst Mol Biol & Genet, Dept Mol Oncogenet, Kiev, Ukraine..
    Sarkisyan, Daniil
    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. Inst Mol Biol & Genet, Dept Human Genet, Kiev, Ukraine..
    Yakovleva, Tatiana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Tonevitsky, Alex
    Moscow MV Lomonosov State Univ, Moscow, Russia.;Higher Sch Econ, Moscow, Russia..
    Marklund, Niklas
    Lund Univ, Univ Hosp Southern Sweden, Div Neurosurg, Dept Clin Sci, Lund, Sweden..
    Ossipov, Michael H.
    Univ Arizona, Hlth Sci Ctr, Dept Pharmacol, Tucson, AZ USA..
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Differential effects of left and right neuropathy on opioid gene expression in lumbar spinal cord2018In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1695, p. 78-83Article in journal (Refereed)
    Abstract [en]

    The endogenous opioid system (EOS) controls the processing of nociceptive stimuli and is a pharmacological target for opioids. Alterations in expression of the EOS genes under neuropathic pain condition may account for low efficacy of opioid drugs. We here examined whether EOS expression patterns are altered in the lumbar spinal cord of the rats with spinal nerve ligation (SNL) as a neuropathic pain model. Effects of the left- and right-side SNL on expression of EOS genes in the ipsi- and contralateral spinal domains were analysed. The SNL-induced changes were complex and different between the genes; between the dorsal and ventral spinal domains; and between the left and right sides of the spinal cord. Prodynorphin (Pdyn) expression was upregulated in the ipsilateral dorsal domains by each the left and right-side SNL, while changes in expression mu-opioid receptor (Oprm I) and proenkephalin (Penk) genes were dependent on the SNL side. Changes in expression of the Pdyn and kappa-opioid receptor (Oprk1) genes were coordinated between the ipsi- and contralateral sides. Withdrawal response thresholds, indicators of mechanical allodynia correlated negatively with Pdyn expression in the right ventral domain after right side SNL. These findings suggest multiple roles of the EOS gene products in spinal sensitization and changes in motor reflexes, which may differ between the left and right sides. (C) 2018 Elsevier B.V. All rights reserved.

  • 16.
    Kononenko, Olga
    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.
    Stålhandske, Lada
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Zarelius, Ann
    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.
    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.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery. Lund Univ, Dept Clin Sci Neurosurg, Skane Univ Hosp, EA Blocket,4th Floor,Box 188, S-22100 Lund, Sweden.
    Focal traumatic brain injury induces neuroplastic molecular responses in lumbar spinal cord2019In: Restorative Neurology and Neuroscience, ISSN 0922-6028, E-ISSN 1878-3627, Vol. 37, no 2, p. 87-96Article in journal (Refereed)
    Abstract [en]

    Background/Objectives: Motor impairment induced by traumatic brain injury (TBI) may be mediated through changes in spinal molecular systems regulating neuronal plasticity. We assessed whether a focal controlled cortical impact (CCI) TBI in the rat alters expression of the Tgfb1, c-Fos, Bdnf and Gap43 neuroplasticity genes in lumbar spinal cord.

    Approach/Methods: Adult male Sprague-Dawley rats (n = 8) were subjected to a right-side CCI over the anterior sensorimotor hindlimb representation area or sham-injury (n=8). Absolute expression levels of Tgfb1, c-Fos, Bdnf, and Gapd43 genes were measured by droplet digital PCR in ipsi- and contralesional, dorsal and ventral quadrants of the L4 and L5 spinal cord. The neuronal activity marker c-Fos was analysed by immunohistochemistry in the dorsal L4 and L5 segments. The contra- vs. ipsilesional expression pattern was examined as the asymmetry index, AI.

    Results: The Tgfb1 mRNA levels were significantly higher in the CCI vs. sham-injured rats, and in the contra- vs. ipsilesional dorsal domains in the CCI group. The number of c-Fos-positive cells was elevated in the L4 and L5 segments; and on the contralesional compared to the ipsilesional side in the CCI group. The c-Fos AI in the dorsal laminae was significantly increased by CCI.

    Conclusions: The results support the hypothesis that focal TBI induces plastic alterations in the lumbar spinal cord that may contribute to either motor recovery or maladaptive motor responses.

  • 17.
    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)
  • 18. 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.

  • 19.
    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)
  • 20.
    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.

  • 21.
    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.

  • 22.
    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)
1 - 22 of 22
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