Change search
Refine search result
12 1 - 50 of 86
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1.
    Adjan, V. V.
    et al.
    Department of Anatomy and Neurobiology, University of Kentucky, Lexington, USA.
    Hauser, K. F.
    Department of Anatomy and Neurobiology, University of Kentucky, Lexington, USA and Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, USA.
    Bakalkin, Georgy
    Experimental Alcohol and Drug Addiction Research Section, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Yakovleva, T.
    Experimental Alcohol and Drug Addiction Research Section, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Gharibyan, A.
    Experimental Alcohol and Drug Addiction Research Section, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Scheff, S. W.
    Department of Anatomy and Neurobiology, 800 Rose Street, MS209, University of Kentucky, Lexington, KY 40536-0298, USA; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536-0298, USA and Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536-0298, USA.
    Knapp, P. E.
    Department of Anatomy and Neurobiology, 800 Rose Street, MS209, University of Kentucky, Lexington, KY 40536-0298, USA and Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536-0298, USA.
    Caspase-3 activity is reduced after spinal cord injury in mice lacking dynorphin: differential effects on glia and neurons2007In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 148, no 3, p. 724-36Article in journal (Refereed)
    Abstract [en]

    Dynorphins are endogenous opioid peptide products of the prodynorphin gene. An extensive literature suggests that dynorphins have deleterious effects on CNS injury outcome. We thus examined whether a deficiency of dynorphin would protect against tissue damage after spinal cord injury (SCI), and if individual cell types would be specifically affected. Wild-type and prodynorphin(-/-) mice received a moderate contusion injury at 10th thoracic vertebrae (T10). Caspase-3 activity at the injury site was significantly decreased in tissue homogenates from prodynorphin(-/-) mice after 4 h. We examined frozen sections at 4 h post-injury by immunostaining for active caspase-3. At 3-4 mm rostral or caudal to the injury, >90% of all neurons, astrocytes and oligodendrocytes expressed active caspase-3 in both wild-type and knockout mice. At 6-7 mm, there were fewer caspase-3(+) oligodendrocytes and astrocytes than at 3-4 mm. Importantly, caspase-3 activation was significantly lower in prodynorphin(-/-) oligodendrocytes and astrocytes, as compared with wild-type mice. In contrast, while caspase-3 expression in neurons also declined with further distance from the injury, there was no effect of genotype. Radioimmunoassay showed that dynorphin A(1-17) was regionally increased in wild-type injured versus sham-injured tissues, although levels of the prodynorphin processing product Arg(6)-Leu-enkephalin were unchanged. Our results indicate that dynorphin peptides affect the extent of post-injury caspase-3 activation, and that glia are especially sensitive to these effects. By promoting caspase-3 activation, dynorphin peptides likely increase the probability of glial apoptosis after SCI. While normally beneficial, our findings suggest that prodynorphin or its peptide products become maladaptive following SCI and contribute to secondary injury.

  • 2.
    Ahmed, Aisha S.
    et al.
    Karolinska Inst, Dept Clin Neurosci, Nobel Vag 9, S-17177 Stockholm, Sweden.
    Gedin, Per
    Lowenstromska Hosp, Ortho Ctr Stockholm, S-19489 Upplands Vasby, Sweden.
    Hugo, Anders
    Lowenstromska Hosp, Ortho Ctr Stockholm, S-19489 Upplands Vasby, Sweden.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kanar, Alkass
    Karolinska Inst, Dept Oncol Pathol, S-17177 Stockholm, Sweden;Swedish Natl Board Forens Med, S-17165 Solna, Sweden.
    Hart, David A.
    Univ Calgary, McCaig Inst Bone & Joint Hlth, Calgary, AB T2N 1N4, Canada.
    Druid, Henrik
    Karolinska Inst, Dept Oncol Pathol, S-17177 Stockholm, Sweden;Swedish Natl Board Forens Med, S-17165 Solna, Sweden.
    Svensson, Camilla
    Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden.
    Kosek, Eva
    Karolinska Inst, Dept Clin Neurosci, Nobel Vag 9, S-17177 Stockholm, Sweden;Stockholm Spine Ctr, Lowenstromska Hosp, S-19489 Upplands Vasby, Sweden.
    Activation of NF-kappa B in Synovium versus Cartilage from Patients with Advanced Knee Osteoarthritis: A Potential Contributor to Inflammatory Aspects of Disease Progression2018In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 201, no 7, p. 1918-1927Article in journal (Refereed)
    Abstract [en]

    The aim was to assess the activation and association of the NF-kappa B system across synovial membrane (SM) and articular cartilage (AC) in patients with knee osteoarthritis (OA) and ascertain its potential effects on catabolic mediator expression in advanced OA. SM and AC were obtained from 40 OA patients undergoing total knee arthroplasty and from 19 postmortem control subjects. NF-kappa B subunit RelA in nuclear and cytosolic fractions and NF-kappa B1-DNA binding in nuclear extracts was assessed by ELISA, whereas NFKB1, RELA, IL-8, IL-6, and MMP3 gene expression were analyzed by reverse transcriptase-quantitative PCR in tissues. We observed higher SM nuclear RelA protein levels and upregulated NF-kappa B1-DNA binding in OA patients compared with postmortem controls. However, in AC, lower nuclear RelA levels were observed compared with cytosolic extracts in patients. Nuclear RelA levels correlated positively with NF-kappa B1-DNA binding in SM and AC in patients. SM RELA and MMP3 mRNA levels were upregulated, whereas IL-8 and IL-6 as well as AC RELA were downregulated in patients compared with controls. In SM, nuclear RelA levels correlated positively with MMP3 gene expression in patients. A negative correlation was observed between SM nuclear RelA levels and AC NF-kappa B1-DNA binding, and SM nuclear NF-kappa B1-DNA binding correlated negatively with AC MMP3 and NFKB1 mRNA levels in patients. These findings highlight NF-kappa B-triggered cross-talk and feedback mechanisms between SM and AC in OA. Further, our findings strongly support a role for an activated NF-kappa B system in the transcriptional mechanism of inflammatory processes, especially in SM of patients with advanced OA.

  • 3. Ahmed, Aisha S
    et al.
    Li, Jian
    Erlandsson-Harris, Helena
    Stark, André
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mahmood, Ahmed
    Suppression of pain and joint destruction by inhibition of the proteasome system in experimental osteoarthritis2012In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 153, no 1, p. 18-26Article in journal (Refereed)
    Abstract [en]

    Osteoarthritis is a degenerative joint disease with pain and loss of joint function as major pathological features. Recent studies show that proteasome inhibitors reduce pain in various pathological conditions. We evaluated the effects of MG132, a reversible proteasome inhibitor on pain and joint destruction in a rat model of osteoarthritis. Osteoarthritis was induced by intraarticular injection of monosodium iodoacetate into the rat knee. Knee joint stiffness was scored and nociception was evaluated by mechanical pressure applied to the respective hind paw. Knee joint destruction was assessed by radiological and histological analyses. Expression of matrix metalloproteinase-3 (MMP-3) was analyzed by quantitative reverse transcription polymerase chain reaction in the knee articular cartilage. Expression of substance P (SP) and calcitonin gene-related peptide (CGRP) was studied in the dorsal root ganglia (L4–L6) by quantitative reverse transcription polymerase chain reaction and in the knee joints by immunohistochemistry. Our results indicate that daily treatment of osteoarthritic rats with MG132 significantly increases their mobility while the swelling, pain thresholds, and pathological features of the affected joints were reduced. Furthermore, the upregulated expression of MMP-3, SP, and CGRP in the arthritic rats was normalized by MG132 administration. We conclude that the proteasome inhibitor MG132 reduces pain and joint destruction, probably by involving the peripheral nervous system, and that changes in SP and CGRP expression correlate with alterations in behavioural responses. Our findings suggest that nontoxic proteasome inhibitors may represent a novel pharmacotherapy for osteoarthritis.

  • 4.
    Ahmed, Aisha Siddiqah
    et al.
    Karolinska Inst, Dept Clin Neurosci, S-17177 Stockholm, Sweden.
    Ahmed, Mahmood
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Family & Community Med, Huddinge, Sweden.
    Li, Jian
    Karolinska Inst, Karolinska Univ Hosp, Dept Mol Med & Surg, Stockholm, Sweden.
    Gu, Harvest F
    Karolinska Inst, Karolinska Univ Hosp, Dept Mol Med & Surg, Stockholm, Sweden.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Stark, André
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden.
    Harris, Helena Erlandsson
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Ctr Mol Med, Stockholm, Sweden.
    Proteasome inhibitor MG132 modulates inflammatory pain by central mechanisms in adjuvant arthritis.2017In: International journal of rheumatic diseases, ISSN 1756-185X, Vol. 20, no 1, p. 25-32Article in journal (Refereed)
    Abstract [en]

    AIMS: In rheumatoid arthritis (RA), pain and inflammation are initial symptoms followed by various degrees of bone and cartilage destruction. Previously, we have shown that reversible proteasome inhibitor MG132 attenuates pain and joint inflammation in a rat model of adjuvant-arthritis. Our present study aims to study the effects of MG132 on molecular changes in the dorsal root ganglia (DRG) and in the spinal cord (SC) using the same animal model.

    METHODS: Arthritis was induced by heat-killed Mycobacterium butyricum in rats. The expression of substance P (SP) was analyzed by quantitative reverse transcription polymerase chain reaction and immunohistochemistry in DRG and in the SC. The nuclear factor-κB (NF-κB) DNA-binding activity in the SC was analyzed by electromobility shift assay.

    RESULTS: Arthritic rats treated daily with MG132 demonstrated a marked reduction of SP gene expression in the DRG and number of SP-positive cells was reduced. In the spinal cord of arthritic rats elevated SP messenger RNA levels were normalized and NF-κB-DNA-binding activity was down-regulated in arthritic rats treated with MG132.

    CONCLUSION: Our results indicate that proteasome inhibitor MG132 attenuates pain in adjuvant arthritis by targeting the sensory neuropeptide substance P in the peripheral and central nervous systems. These effects may be mediated through the inhibition of NF-κB activation.

  • 5.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The left-right neurohormonal regulation in the brain: Lateralized endogenous opioid system2014In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 211, p. 12-12Article in journal (Other academic)
  • 6.
    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, Z.
    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)
  • 7.
    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.
    Jezierska, Justyna
    Depoorter, Cloë
    Verschuuren-Bemelmans, Corien
    Bazov, Igor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Artemenko, Konstantin A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
    Yakovleva, Tatjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Dooijes, Dennis
    Van de Warrenburg, Bart P. C.
    Zubarev, Roman A.
    Kremer, Berry
    Knapp, Pamela E.
    Hauser, Kurt F.
    Wijmenga, Cisca
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sinke, Richard J.
    Verbeek, Dineke S.
    Prodynorphin mutations cause the neurodegenerative disorder spinocerebellar ataxia type 23.2010In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 87, no 5, p. 593-603Article in journal (Refereed)
    Abstract [en]

    Spinocerebellar ataxias (SCAs) are dominantly inherited neurodegenerative disorders characterized by progressive cerebellar ataxia and dysarthria. We have identified missense mutations in prodynorphin (PDYN) that cause SCA23 in four Dutch families displaying progressive gait and limb ataxia. PDYN is the precursor protein for the opioid neuropeptides, α-neoendorphin, and dynorphins A and B (Dyn A and B). Dynorphins regulate pain processing and modulate the rewarding effects of addictive substances. Three mutations were located in Dyn A, a peptide with both opioid activities and nonopioid neurodegenerative actions. Two of these mutations resulted in excessive generation of Dyn A in a cellular model system. In addition, two of the mutant Dyn A peptides induced toxicity above that of wild-type Dyn A in cultured striatal neurons. The fourth mutation was located in the nonopioid PDYN domain and was associated with altered expression of components of the opioid and glutamate system, as evident from analysis of SCA23 autopsy tissue. Thus, alterations in Dyn A activities and/or impairment of secretory pathways by mutant PDYN may lead to glutamate neurotoxicity, which underlies Purkinje cell degeneration and ataxia. PDYN mutations are identified in a small subset of ataxia families, indicating that SCA23 is an infrequent SCA type (~0.5%) in the Netherlands and suggesting further genetic SCA heterogeneity.

  • 8.
    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)
  • 9.
    Bakalkin, Georgy
    et al.
    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.
    Dysregulation of the dynorphin/kappa-opioid receptor system in cortical areas of human alcoholics: shift in epigenetic mechanisms2012In: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 36, no Suppl. 1, p. 357A-357AArticle in journal (Other academic)
  • 10.
    Bakalkin, Georgy
    et al.
    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.
    The dynorphin/kappa-opioid receptor system: molecular and epigenetic adaptations in emotional circuitry of alcoholics2016In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 26, p. S152-S152Article in journal (Other academic)
  • 11.
    Bakalkin, Georgy
    et al.
    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.
    Bazov, Igor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brain Area-Specific Dysregulation Of The Dynorphin/Kappa-Opioid Receptor System In Human Alcoholics: Implications For Pathogenesis2014In: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 38, p. 345A-345AArticle in journal (Other academic)
  • 12.
    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.
    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.
    Taqi, Mumtaz Malik
    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.
    Verbeek, Dineke
    Rajkowska, Grazyna
    Syvänen, Ann-Christine
    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.
    Neuronal Expression of Opioid Gene is Regulated by Genetically Controlled Epigenetic and Transcriptional Mechanisms in Addicted Human BrainManuscript (preprint) (Other academic)
  • 13.
    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.

  • 14.
    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.
    Hussain, M. Z.
    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, V. M.
    Mayo Clin, Dept Psychiat & Psychol, Rochester, MN 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.
    THE ENDOGENOUS OPIOID SYSTEM: DYSREGULATION IN THE STRIATUM OF HUMAN ALCOHOLICS2015In: Alcohol and Alcoholism, ISSN 0735-0414, E-ISSN 1464-3502, Vol. 50Article in journal (Other academic)
  • 15.
    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.

  • 16.
    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.

  • 17.
    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.

  • 18.
    Bivehed, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Strömvall, Robert
    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.
    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.
    Region-specific bioconversion of dynorphin neuropeptide detected by in situ histochemistry and MALDI imaging mass spectrometry2017In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 87, p. 20-27Article in journal (Refereed)
    Abstract [en]

    Brain region-specific expression of proteolytic enzymes can control the biological activity of endogenous neuropeptides and has recently been targeted for the development of novel drugs, for neuropathic pain, cancer, and Parkinson's disease. Rapid and sensitive analytical methods to profile modulators of enzymatic activity are important for finding effective inhibitors with high therapeutic value. Combination of in situ enzyme histochemistry with MALDI imaging mass spectrometry allowed developing a highly sensitive method for analysis of brain-area specific neuropeptide conversion of synthetic and endogenous neuropeptides, and for selection of peptidase inhibitors that differentially target conversion enzymes at specific anatomical sites. Conversion and degradation products of Dynorphin B as model neuropeptide and effects of peptidase inhibitors applied to native brain tissue sections were analyzed at different brain locations. Synthetic dynorphin B (2 pmol) was found to be converted to the N-terminal fragments on brain sections whereas fewer C-terminal fragments were detected. N-ethylmaleimide (NEM), a non-selective inhibitor of cysteine peptidases, almost completely blocked the conversion of dynorphin B to dynorphin B(1-6; Leu-Enk-Arg), (1-9), (2-13), and (7-13). Proteinase inhibitor cocktail, and also incubation with acetic acid displayed similar results. Bioconversion of synthetic dynorphin B was region-specific producing dynorphin B(1-7) in the cortex and dynorphin B (2-13) in the striatum. Enzyme inhibitors showed region-and enzyme-specific inhibition of dynorphin bioconversion. Both phosphoramidon (inhibitor of the known dynorphin converting enzyme neprilysin) and opiorphin (inhibitor of neprilysin and aminopeptidase N) blocked cortical bioconversion to dynorphin B(1-7), wheras only opiorphin blocked striatal bioconversion to dynorphin B(2-13). This method may impact the development of novel therapies with aim to strengthen the effects of endogenous neuropeptides under pathological conditions such as chronic pain. Combining histochemistry and MALDI imaging MS is a powerful and sensitive tool for the study of inhibition of enzyme activity directly in native tissue sections. (C) 2016 The Authors. Published by Elsevier Inc.

  • 19. Chefer, Vladimir
    et al.
    Meis, Jennifer
    Wang, Grace
    Kuzmin, Alexander
    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.
    Shippenberg, Toni
    Repeated exposure to moderate doses of ethanol augments hippocampal glutamate neurotransmission by increasing release2011In: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 16, no 2, p. 229-237Article in journal (Refereed)
    Abstract [en]

    The present study used conventional and quantitative microdialysis to assess glutamatergic and GABAergic neurotransmission in the hippocampal CA3 area of the rat following a moderate-dose ethanol treatment regimen. Male Wistar rats received 3.4 g/kg of ethanol or water for 6 days via gastric gavage. Microdialysis experiments commenced 2 days later. Basal and depolarization-induced glutamate overflow were significantly elevated in ethanol-treated animals. Basal and depolarization-induced gamma-aminobutyric acid (GABA) overflow were unaltered. Quantitative no-net-flux microdialysis was used to determine if changes in dialysate glutamate levels following ethanol administration are due to an increase in release or a decrease in uptake. To confirm the validity of this method for quantifying basal glutamate dynamics, extracellular concentrations of glutamate and the extraction fraction, which reflects changes in analyte clearance, were quantified in response to retro-dialysis of the glutamate uptake blocker trans-pyrrolidine-2,4-dicarboxylic acid (tPDC). tPDC significantly decreased the extraction fraction for glutamate, resulting in augmented extracellular glutamate concentrations. Repeated ethanol administration did not alter the glutamate extraction fraction. However, extracellular glutamate concentrations were significantly elevated, indicating that glutamate release is increased as a consequence of repeated ethanol administration. These data demonstrate that repeated bouts of moderate ethanol consumption alter basal glutamate dynamics in the CA3 region of the dorsal hippocampus. Basal glutamate release is augmented, whereas glutamate uptake is unchanged. Furthermore, they suggest that dysregulation of glutamate transmission in this region may contribute to the previously documented deficits in cognitive function associated with moderate dose ethanol use.

  • 20. Chizhmakov, Igor
    et al.
    Kulyk, Vyacheslav
    Khasabova, Iryna
    Khasabov, Sergey
    Simone, Donald
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gordienko, Dmitri
    Verkhratsky, Alexei
    Krishtal, Oleg
    Molecular mechanism for opioid dichotomy: bidirectional effect of mu-opioid receptors on P2X(3) receptor currents in rat sensory neurones2015In: Purinergic Signalling Purinergic Signalling, ISSN 1573-9538, E-ISSN 1573-9546, Vol. 11, no 2, p. 171-181Article in journal (Refereed)
    Abstract [en]

    Here, we describe a molecular switch associated with opioid receptors-linked signalling cascades that provides a dual opioid control over P2X(3) purinoceptor in sensory neurones. Leu-enkephalin inhibited P2X(3)-mediated currents with IC50 similar to 10 nM in similar to 25 % of small nociceptive rat dorsal root ganglion (DRG) neurones. In contrast, in neurones pretreated with pertussis toxin leu-enkephalin produced stable and significant increase of P2X(3) currents. All effects of opioid were abolished by selective mu-opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), nonselective inhibitor naloxone, and by PLC inhibitor U73122. Thus, we discovered a dual link between purinoceptors and mu-opioid receptors: the latter exert both inhibitory (pertussis toxin-sensitive) and stimulatory (pertussis toxin-insensitive) actions on P2X(3) receptors through phospholipase C (PLC)-dependent pathways. This dual opioid control of P2X(3) receptors may provide a molecular explanation for dichotomy of opioid therapy. Pharmacological control of this newly identified facilitation/inhibition switch may open new perspectives for the adequate medical use of opioids, the most powerful pain-killing agents known today.

  • 21. Dong, Li
    et al.
    Bilbao, Ainhoa
    Laucht, Manfred
    Henriksson, Richard
    Yakovleva, Tatjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ridinger, Monika
    Desrivieres, Sylvane
    Clarke, Toni-Kim
    Lourdusamy, Anbarasu
    Smolka, Michael N.
    Cichon, Sven
    Blomeyer, Dorothea
    Treutlein, Jens
    Perreau-Lenz, Stephanie
    Witt, Stephanie
    Leonardi-Essmann, Fernando
    Wodarz, Norbert
    Zill, Peter
    Soyka, Michael
    Albrecht, Urs
    Rietschel, Marcella
    Lathrop, Mark
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Spanagel, Rainer
    Schumann, Gunter
    Effects of the Circadian Rhythm Gene Period 1 (Per1) on Psychosocial Stress-Induced Alcohol Drinking2011In: American Journal of Psychiatry, ISSN 0002-953X, E-ISSN 1535-7228, Vol. 168, no 10, p. 1090-1098Article in journal (Refereed)
    Abstract [en]

    Objective: Circadian and stress-response systems mediate environmental changes that affect alcohol drinking. Psychosocial stress is an environmental risk factor for alcohol abuse. Circadian rhythm gene period 1(Per1) is targeted by stress hormones and is transcriptionally activated in corticotropin releasing factor-expressing cells. The authors hypothesized that Per1 is involved in integrating stress response and circadian rhythmicity and explored its relevance to alcohol drinking.

    Method: In mice, the effects of stress on ethanol intake in mPer1-mutant and wild-type mice were assessed. In humans, single nucleotide polymorphisms (SNPs) in hPer1 were tested for association with alcohol drinking behavior in 273 adolescents and an adult case-control sample of 1,006 alcohol-dependent patients and 1,178 comparison subjects. In vitro experiments were conducted to measure genotype-specific expression and transcription factor binding to hPer1.

    Results: The mPer1-mutant mice showed enhanced alcohol consumption in response to social defeat stress relative to their wild-type littermates. An association with the frequency of heavy drinking in adolescents with the hPer1 promoter SNP rs3027172 and with psychosocial adversity was found. There was significant interaction between the rs3027172 genotype and psychosocial adversity on this drinking measure. In a confirmatory analysis, association of hPer1 rs3027172 with alcohol dependence was shown. Cortisol-induced transcriptional activation of hPer1 was reduced in human B-lymphoblastoid cells carrying the risk genotype of rs3027172. Binding affinity of the transcription factor Snail1 to the risk allele of the hPer1 SNP rs3027172 was also reduced.

    Conclusions: The findings indicate that the hPer1 gene regulates alcohol drinking behavior during stressful conditions and provide evidence for underlying neurobiological mechanisms.

  • 22.
    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.

  • 23. El-Hage, Nazira
    et al.
    Bruce-Keller, Annadora J
    Yakovleva, Tatiana
    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.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Knapp, Pamela E
    Hauser, Kurt F
    Morphine exacerbates HIV-1 Tat-induced cytokine production in astrocytes through convergent effects on [Ca(2+)](i), NF-kappaB trafficking and transcription2008In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 3, no 12, p. e4093-Article in journal (Refereed)
    Abstract [en]

    Astroglia are key cellular sites where opiate drug signals converge with the proinflammatory effects of HIV-1 Tat signals to exacerbate HIV encephalitis. Despite this understanding, the molecular sites of convergence driving opiate-accelerated neuropathogenesis have not been deciphered. We therefore explored potential points of interaction between the signaling pathways initiated by HIV-1 Tat and opioids in striatal astrocytes. Profiling studies screening 152 transcription factors indicated that the nuclear factor-kappa B (NF-kappaB) subunit, c-Rel, was a likely candidate for Tat or Tat plus opiate-induced increases in cytokine and chemokine production by astrocytes. Pretreatment with the NF-kappaB inhibitor parthenolide provided evidence that Tat+/-morphine-induced release of MCP-1, IL-6 and TNF-alpha by astrocytes is NF-kappaB dependent. The nuclear export inhibitor, leptomycin B, blocked the nucleocytoplasmic shuttling of NF-kappaB; causing p65 (RelA) accumulation in the nucleus, and significantly attenuated cytokine production in Tat+/-morphine exposed astrocytes. Similarly, chelating intracellular calcium ([Ca(2+)](i)) blocked Tat+/-morphine-evoked MCP-1 and IL-6 release, while artificially increasing the concentration of extracellular Ca(2+) reversed this effect. Taken together, these results demonstrate that: 1) exposure to Tat+/-morphine is sufficient to activate NF-kappaB and cytokine production, 2) the release of MCP-1 and IL-6 by Tat+/-morphine are highly Ca(2+)-dependent, while TNF-alpha appears to be less affected by the changes in [Ca(2+)](i), and 3) in the presence of Tat, exposure to opiates augments Tat-induced NF-kappaB activation and cytokine release through a Ca(2+)-dependent pathway.

  • 24.
    Henriksson, Richard
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Backman, Cristina M
    Harvey, Brandon K
    Kadyrova, Helena
    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.
    Shippenberg, Toni S
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    PDYN, a gene implicated in brain/mental disorders, is targeted by REST in the adult human brain2014In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1839, no 11, p. 1226-1232Article in journal (Refereed)
    Abstract [en]

    The dynorphin kappa-opioid receptor system is implicated in mental health and brain/mental disorders. However, despite accumulating evidence that PDYN and/or dynorphin peptide expression is altered in the brain of individuals with brain/mental disorders, little is known about transcriptional control of PDYN in humans. In the present study, we show that PDYN is targeted by the transcription factor REST in human neuroblastoma SH-SY5Y cells and that that interfering with REST activity increases PDYN expression in these cells. We also show that REST binding to PDYN is reduced in the adult human brain compared to SH-SY5Y cells, which coincides with higher PDYN expression. This may be related to MIR-9 mediated down-regulation of REST as suggested by a strong inverse correlation between REST and MIR-9 expression. Our results suggest that REST represses PDYN expression in SH-SY5Y cells and the adult human brain and may have implications for mental health and brain/mental disorders.

  • 25.
    Henriksson, Richard
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kuzmin, Alexander
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ökvist, Anna
    Harper, Clive
    Sheedy, Donna
    Garrick, Therese
    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.
    Elevated synaptophysin I in the prefrontal cortex of human chronic alcoholics2008In: Synapse, ISSN 0887-4476, E-ISSN 1098-2396, Vol. 62, no 11, p. 829-33Article in journal (Refereed)
    Abstract [en]

    Convergent lines of evidence suggest potentiation of glutamatergic synapses after chronic ethanol exposure, and indicate that the presynaptic effect hereof is on modulators of synaptic strength rather than on executors of glutamate release. To address this hypothesis in the context of ethanol dependence in humans, we used semiquantitative immunoblotting to compare the immunoreactivities of synaptophysin I, syntaxin 1A, synaptosome-associated protein 25, and vesicle-associated membrane protein in the prefrontal and motor cortices between chronic alcoholics and control subjects. We found a region-specific elevation in synaptophysin I immunoreactivity in the prefrontal cortex of alcoholics, but detected no significant differences between the groups in the immunoreactivities of the other three proteins. Our findings are consistent with an effect of repeated ethanol exposure on modulators of synaptic strength but not on executors of glutamate release, and suggest a role for synaptophysin I in the enduring neuroplasticity in the prefrontal cortical glutamate circuitry that is associated with ethanol dependence.

  • 26.
    Hirth, N.
    et al.
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth Mannheim, Inst Psychopharmacol, D-69115 Heidelberg, Germany..
    Sommer, W. H.
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth Mannheim, Inst Psychopharmacol, D-69115 Heidelberg, Germany..
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Spanagel, R.
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth Mannheim, Inst Psychopharmacol, D-69115 Heidelberg, Germany..
    Hansson, A. C.
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth Mannheim, Inst Psychopharmacol, D-69115 Heidelberg, Germany..
    OPIOIDERGIC MECHANISM IN ALCOHOLISM: TRANSLATIONAL STUDIES IN RODENTS AND HUMANS2015In: Alcohol and Alcoholism, ISSN 0735-0414, E-ISSN 1464-3502, Vol. 50Article in journal (Other academic)
  • 27.
    Ho, Ada M-C
    et al.
    Mayo Clin, Dept Psychiat & Psychol, Rochester, MN, USA.
    Geske, Jennifer R.
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN, USA.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Winham, Stacey J.
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN, USA.
    Karpyak, Victor M.
    Mayo Clin, Dept Psychiat & Psychol, Rochester, MN, USA.
    Correlations between sex-related hormones, alcohol dependence and alcohol craving2019In: Drug And Alcohol Dependence, ISSN 0376-8716, E-ISSN 1879-0046, Vol. 197, p. 183-190Article in journal (Refereed)
    Abstract [en]

    Background: Sex-related differences in the susceptibility, progression, and treatment response in alcohol-dependent subjects have been repeatedly reported. In this study, we aimed to investigate the associations of the sex-related hormone/protein levels with alcohol dependence (AD) and alcohol craving in male and female subjects.

    Methods: Plasma sex-related hormones (estradiol, estrone, total testosterone, progesterone, follicle stimulated hormone [FSH], luteinizing hormone), and sex hormone binding globulin were measured by mass spectrometry or automated immunoassays from 44 recently-abstained subjects (29 males and 15 females; mean age = 45.9 ± 15.6) meeting DSM-IV-TR criteria for AD and 44 age-, sex- and race-matched non-AD controls. Conditional logistic regression was conducted to examine the association of sex-related hormone and protein levels with AD risk, accounting for matching variables. Their associations with alcohol craving scales (Penn Alcohol Craving Scale and Inventory of Drug-Taking Situations) were assessed in AD subjects.

    Results: Plasma FSH level was significantly higher in AD males (10.3 ± 9.8 IU/L) than control males (8.0 ± 15.9 IU/L; p = 0.005, pcorrected = 0.035). We also found a significant inverse correlation of FSH level with propensity to drink in negative emotional situations (Spearman’s rho=-.540; p = 0.021) and positive correlations between progesterone level and craving intensity (Spearman’s rho=.464; p = 0.020) and between total testosterone level and propensity to drink under temptations (adjusted for no-drinking days; β=6.496; p = 0.041) in AD males.

    Conclusions: These results suggest that FSH, progesterone, and testosterone levels may be associated with AD and alcohol craving in AD males. Future research is needed to replicate these findings and investigate the underlying biological mechanisms.

  • 28.
    Hussain, Zubair Muhammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fitting, Sylvia
    Watanabe, Hiroyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Usynin, Ivan
    Yakovleva, Tatjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Knapp, Pamela E.
    Scheff, Stephen W.
    Hauser, Kurt F.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lateralized Response of Dynorphin A Peptide Levels after Traumatic Brain Injury2012In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 29, no 9, p. 1785-1793Article in journal (Refereed)
    Abstract [en]

    Traumatic brain injury (TBI) induces a cascade of primary and secondary events resulting in impairment of neuronal networks that eventually determines clinical outcome. The dynorphins, endogenous opioid peptides, have been implicated in secondary injury and neurodegeneration in rodent and human brain. To gain insight into the role of dynorphins in the brain's response to trauma, we analyzed short-term (1-day) and long-term (7-day) changes in dynorphin A (Dyn A) levels in the frontal cortex, hippocampus, and striatum, induced by unilateral left-side or right-side cortical TBI in mice. The effects of TBI were significantly different from those of sham surgery (Sham), while the sham surgery also produced noticeable effects. Both sham and TBI induced short-term changes and long-term changes in all three regions. Two types of responses were generally observed. In the hippocampus, Dyn A levels were predominantly altered ipsilateral to the injury. In the striatum and frontal cortex, injury to the right (R) hemisphere affected Dyn A levels to a greater extent than that seen in the left (L) hemisphere. The R-TBI but not L-TBI produced Dyn A changes in the striatum and frontal cortex at 7 days after injury. Effects of the R-side injury were similar in the two hemispheres. In naive animals, Dyn A was symmetrically distributed between the two hemispheres. Thus, trauma may reveal a lateralization in the mechanism mediating the response of Dyn A-expressing neuronal networks in the brain. These networks may differentially mediate effects of left and right brain injury on lateralized brain functions.

  • 29. Jezierska, Justyna
    et al.
    Stevanin, Giovanni
    Watanabe, Hiroyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fokkens, Michiel R
    Zagnoli, Fabien
    Kok, Jérôme
    Goas, Jean-Yves
    Bertrand, Pierre
    Robin, Christophe
    Brice, Alexis
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Durr, Alexandra
    Verbeek, Dineke S
    Identification and characterization of novel PDYN mutations in dominant cerebellar ataxia cases.2013In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 260, no 7, p. 1807-1812Article in journal (Refereed)
    Abstract [en]

    We have recently identified missense mutations in prodynorphin (PDYN), the precursor to dynorphin opioid peptides, as the cause for spinocerebellar ataxia (SCA23) in Dutch ataxia cases. We report a screen of PDYN for mutations in 371 cerebellar ataxia cases, which had a positive family history; most are of French origin. Sequencing revealed three novel putative missense mutations and one heterozygous two-base pair deletion in four independent SCA patients. These variants were absent in 400 matched controls and are located in the highly conserved dynorphin domain. To resolve the pathogenicity of the heterozygous variants, we assessed the peptide production of the mutant PDYN proteins. Two missense mutations raised dynorphin peptide levels, the two-base pair deletion terminated dynorphin synthesis, and one missense mutation did not affect PDYN processing. Given the outcome of our functional analysis, we may have identified at least two novel PDYN mutations in a French and a Moroccan SCA patient. Our data corroborates recent work that also showed that PDYN mutations only account for a small percentage (~0.1 %) of European SCA cases.

  • 30.
    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.

  • 31.
    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.

  • 32.
    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.

  • 33.
    Johansson, Sofia
    et al.
    Section of Alcohol and Drug Dependence Research, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Ekström, Tomas J.
    Section of Alcohol and Drug Dependence Research, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Marinova, Zoya
    Section of Alcohol and Drug Dependence Research, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Ökvist, Anna
    Section of Alcohol and Drug Dependence Research, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Sheedy, Donna
    Discipline of Pathology, University of Sydney, Sydney, NSW, Australia.
    Garrick, Therese
    Discipline of Pathology, University of Sydney, Sydney, NSW, Australia.
    Harper, Clive
    Discipline of Pathology, University of Sydney, Sydney, NSW, Australia.
    Kuzmin, Alexander
    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.
    Dysregulation of cell death machinery in the prefrontal cortex of human alcoholics2009In: International Journal of Neuropsychopharmacology, ISSN 1461-1457, E-ISSN 1469-5111, Vol. 12, no 1, p. 109-115Article in journal (Refereed)
    Abstract [en]

    In human alcoholics, the cell density is decreased in the prefrontal cortex (PFC) and other brain areas. This may be due to persistent activation of cell death pathways. To address this hypothesis, we examined the status of cell death machinery in the dorsolateral PFC in alcoholics. Protein and mRNA expression levels of several key pro- and anti-apoptotic genes were compared in post-mortem samples of 14 male human alcoholics and 14 male controls. The findings do not support the hypothesis. On the contrary, they show that several components of intrinsic apoptotic pathway are decreased in alcoholics. No differences were evident in the motor cortex, which is less damaged in alcoholics and was analysed for comparison. Thus, cell death mechanisms may be dysregulated by inhibition of intrinsic apoptotic pathway in the PFC in human alcoholics. This inhibition may reflect molecular adaptations that counteract alcohol neurotoxicity in cells that survive after many years of alcohol exposure and withdrawal.

  • 34.
    Johansson, Sofia
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Fuchs, Andrea
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Ökvist, Anna
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Karimi, Mohsen
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden and Department of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Harper, Clive
    Discipline of Pathology, University of Sydney, NSW Australia.
    Garrick, Therese
    Discipline of Pathology, University of Sydney, NSW Australia.
    Sheedy, Donna
    Discipline of Pathology, University of Sydney, NSW Australia.
    Hurd, Yasmin
    Departments of Psychiatry and Pharmacology and Biological Chemistry at Mount Sinai School of Medicine, New York, USA.
    Bakalkin, Georgy
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Ekström, Tomas J.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Validation of endogenous controls for quantitative gene expression analysis: Application on brain cortices of human chronic alcoholics2007In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1132, no 1, p. 20-8Article in journal (Refereed)
    Abstract [en]

    Real-time PCR is frequently used for gene expression quantification due to its methodological sensitivity and reproducibility. The gene expression is quantified by normalization to one or more reference genes, usually beta-actin (ACTB), glyceraldehyde-3-phosphate dehydrogenase (GAPD) or to ribosomal RNA (18S). However, different environmental or pathological conditions might also influence the expression of normalizing genes, which could severely skew the interpretation of quantitative results. This study evaluates whether 16 genes frequently used as endogenous controls in expression studies, can serve as such for comparison of human brain tissues of chronic alcoholics and control subjects. The prefrontal and motor cortices that are affected differently by chronic alcohol consumption were analyzed. The reference genes that have no or small differences in expression in alcoholics and control subjects, were found to be specific for each region: beta-actin (ACTB) and ribosomal large P0 (RPLP0) for the prefrontal cortex while importin 8 (IPO8) and RNA polymerase II (POLR2A) for the motor cortex. Four out of sixteen analyzed genes demonstrated significant differences in expression between alcoholics and controls: phosphoglycerate kinase (PGK1), hypoxanthine phosphoribosyl transferase (HPRT1) and peptidylprolyl isomerase A (PPIA) in the motor cortex and beta-2-microglobulin (B2M) in the prefrontal cortex. Our study demonstrates the importance of validation of endogenous control genes prior to real-time PCR analysis of human brain tissues. Prescribed and non-prescribed drugs, pathological or environmental conditions along with alcohol abuse may differentially influence expression of reference genes.

  • 35. Karpyak, V. M.
    et al.
    Preuss, U. W.
    Geske, J.
    Winham, S. J.
    Cunningham, Janet M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Biernacka, J. M.
    Pdyn Rs2281285 Variat Is Associated With The Length Of Sobriety In Alcohol Dependent Subjects2014In: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 38, p. 148A-148AArticle in journal (Other academic)
  • 36.
    Karpyak, V. M.
    et al.
    Mayo Clin, Dept Psychiat & Psychol, Rochester, MN USA..
    Winham, S. J.
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA..
    Biernacka, J. M.
    Mayo Clin, Dept Psychiat & Psychol, Rochester, MN USA.;Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA..
    Geske, J.
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA..
    Cunningham, J. M.
    Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA..
    Abulseoud, O. A.
    Mayo Clin, Dept Psychiat & Psychol, Rochester, MN USA..
    Hall-Flavin, D. K.
    Mayo Clin, Dept Psychiat & Psychol, Rochester, MN USA..
    Loukianova, L. L.
    Mayo Clin, Dept Psychiat & Psychol, Rochester, MN USA..
    Schneekloth, T. D.
    Mayo Clin, Dept Psychiat & Psychol, Rochester, MN USA..
    Frye, M. A.
    Mayo Clin, Dept Psychiat & Psychol, Rochester, MN USA..
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Choi, D-Sup
    Mayo Clin, Dept Psychiat & Psychol, Rochester, MN USA.;Mayo Clin, Dept Mol Pharmacol & Expt Therapeut, Rochester, MN USA..
    Gender Effects on Association Between PDYN Sequence Variation with Alcohol Dependence and Related Phenotypes2015In: Alcohol and Alcoholism, ISSN 0735-0414, E-ISSN 1464-3502, Vol. 50, no Suppl. 1Article in journal (Other academic)
  • 37. Karpyak, V. M.
    et al.
    Winham, S. J.
    Preuss, U. W.
    Zill, P.
    Cunningham, J. M.
    Walker, D. L.
    Geske, J. R.
    Colby, C. L.
    Abulseoud, O. A.
    Hall-Flavin, D. K.
    Loukianova, L. L.
    Schneekloth, T. D.
    Frye, M. A.
    Bazov, Igor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Heit, J. A.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mrazek, D. A.
    Biernacka, J. M.
    PDYN rs2281285 variant is associated with alcohol dependence in male but not female subjects2013In: European psychiatry, ISSN 0924-9338, E-ISSN 1778-3585, Vol. 28, no S1, p. 1344-Article in journal (Other academic)
  • 38. Karpyak, V.
    et al.
    Winham, S.
    Biernacka, J.
    Cunningham, J.
    Walker, D.
    Lewis, K.
    Geske, J.
    Colby, C.
    Abulseoud, O.
    Hall-Flavin, D.
    Loukianova, L.
    Schneekloth, T.
    Frye, M.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mrazek, D.
    Variations in PDYN sequence are associated with negative craving in alcohol dependent subjects2012In: European psychiatry, ISSN 0924-9338, E-ISSN 1778-3585, Vol. 27, no S1Article in journal (Other academic)
  • 39. Karpyak, Victor M.
    et al.
    Winham, Stacey J.
    Biernacka, Joanna M.
    Geske, Jennifer
    Cunningham, Julie M.
    Abulseoud, Osama A.
    Hall-Flavin, Daniel K.
    Loukianova, Larissa L.
    Schneekloth, Terry D.
    Frye, Mark A.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Choi, Doo-Sup
    Variations in PDYN Sequence are Associated with Post-treatment Relapse in Alcohol Dependent Subjects2014In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 75, no 9, p. 352S-352SArticle in journal (Other academic)
  • 40. Karpyak, Victor M
    et al.
    Winham, Stacey J
    Preuss, Ulrich W
    Zill, Peter
    Cunningham, Julie M
    Walker, Denise L
    Lewis, Kriste A
    Geske, Jennifer R
    Colby, Colin L
    Abulseoud, Osama A
    Hall-Flavin, Daniel K
    Loukianova, Larissa L
    Schneekloth, Terry D
    Frye, Mark A
    Bazov, Igor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Heit, John A
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mrazek, David A
    Biernacka, Joanna M
    Association of the PDYN gene with alcohol dependence and the propensity to drink in negative emotional states2013In: International Journal of Neuropsychopharmacology, ISSN 1461-1457, E-ISSN 1469-5111, Vol. 16, no 5, p. 975-985Article in journal (Refereed)
    Abstract [en]

    Synthetic κ-opioid receptor (KOR) agonists induce dysphoric and pro-depressive effects and variations in the KOR (OPRK1) and prodynorphin (PDYN) genes have been shown to be associated with alcohol dependence. We genotyped 23 single nucleotide polymorphisms (SNPs) in the PDYN and OPRK1 genes in 816 alcohol-dependent subjects and investigated their association with: (1) negative craving measured by a subscale of the Inventory of Drug Taking Situations; (2) a self-reported history of depression; (3) the intensity of depressive symptoms measured by the Beck Depression Inventory-II. In addition, 13 of the 23 PDYN and OPRK1 SNPs, which were previously genotyped in a set of 1248 controls, were used to evaluate association with alcohol dependence. SNP and haplotype tests of association were performed. Analysis of a haplotype spanning the PDYN gene (rs6045784, rs910080, rs2235751, rs2281285) revealed significant association with alcohol dependence (p = 0.00079) and with negative craving (p = 0.0499). A candidate haplotype containing the PDYN rs2281285-rs1997794 SNPs that was previously associated with alcohol dependence was also associated with negative craving (p = 0.024) and alcohol dependence (p = 0.0008) in this study. A trend for association between depression severity and PDYN variation was detected. No associations of OPRK1 gene variation with alcohol dependence or other studied phenotypes were found. These findings support the hypothesis that sequence variation in the PDYN gene contributes to both alcohol dependence and the induction of negative craving in alcohol-dependent subjects.

  • 41.
    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.

  • 42.
    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.

  • 43.
    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.

  • 44.
    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.

  • 45. Krishtal, O.
    et al.
    Maximyuk, O.
    Khmyz, V.
    Lindskog, C.
    Vukojevic, V.
    Ivanova, T.
    Rajnisz, A.
    Solecka, J.
    Lipkowski, A.
    Hauser, K.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Opioid neuropeptides make pores in plasma membrane: possible mechanism of signal transduction2014In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 211, p. 12-12Article in journal (Other academic)
  • 46. Kuzmin, A.
    et al.
    Chefer, V.
    Bazov, Igor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Meis, J.
    Ogren, S. O.
    Shippenberg, T.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Upregulated dynorphin opioid peptides mediate alcohol-induced learning and memory impairment2013In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 3, p. e310-Article in journal (Refereed)
    Abstract [en]

    The dynorphin opioid peptides control glutamate neurotransmission in the hippocampus. Alcohol-induced dysregulation of this circuit may lead to impairments in spatial learning and memory. This study examines whether changes in the hippocampal dynorphin and glutamate systems are related, and contribute to impairment of spatial learning and memory in a rat model of cognitive deficit associated with alcohol binge drinking. Hippocampal dynorphins (radioimmunoassay) and glutamate (in vivo microdialysis) were analyzed in Wistar rats exposed to repeated moderate-dose ethanol bouts that impair spatial learning and memory in the Water Maze Task (WMT). The highly selective, long-acting k-opioid receptor (KOR) antagonist nor-binaltorphimine (nor-BNI) was administered systemically or into the hippocampal CA3 region to test a role of dynorphins in alcohol-induced dysregulations in glutamate neurotransmission and behavior in the WMT. The ethanol treatment impaired learning and memory, upregulated dynorphins and increased glutamate overflow in the CA3 region. Administration of nor-BNI after cessation of ethanol exposure reversed ethanol-induced changes in glutamate neurotransmission in animals exposed to ethanol and normalized their performance in the WMT. The findings suggest that impairments of spatial learning and memory by binge-like ethanol exposure are mediated through the KOR activation by upregulated dynorphins resulting in elevation in glutamate levels. Selective KOR antagonists may correct alcohol-induced pathological processes, thus representing a novel pharmacotherapy for treating of ethanol-related cognitive deficits.

  • 47.
    Kuzmin, Alexander
    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.
    Sheedy, Donna
    The Discipline of Pathology, University of Sydney, Sydney, NSF, Australia.
    Garrick, Therese
    The Discipline of Pathology, University of Sydney, Sydney, NSF, Australia.
    Harper, Clive
    The Discipline of Pathology, University of Sydney, Sydney, NSF, Australia.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Expression of pronociceptin and its receptor is downregulated in the brain of human alcoholics2009In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1305, no Suppl. 1, p. S80-85Article in journal (Refereed)
    Abstract [en]

    Animal studies demonstrated a role of neuropeptide nociceptin (NC) and its receptor (opiate receptor like-1, OPRL1) in ethanol-induced reward; activation of the OPRL1 by natural or synthetic ligands reduced ethanol self-administration and prevented relapse to ethanol drinking. The endogenous NC may function in neuronal circuits involved in reinforcing or conditioning effects of ethanol as a "brake" to limit ethanol intake (Roberto, M., Siggins, G.R. 2006. Nociceptin/orphanin FQ presynaptically decreases GABAergic transmission and blocks the ethanol-induced increase of GABA release in central amygdala. Proc. Natl. Acad. Sci. USA 103. 9715-9720), whereas repeated ethanol intake may downregulate the endogenous NC/OPRL1 system resulting in activation of ethanol consumption. To address this hypothesis, we evaluated whether expression of the pronociceptin (PNOC) and OPRL1 genes is altered in human alcoholics. mRNAs transcribed from these genes were analyzed by quantitative RT-PCR in the prefrontal and orbitofrontal cortices, central amygdala and hippocampal dentate gyrus, structures controlling alcohol consumption. Reduction in PNOC mRNA (1.7-fold) was found in the hippocampus of alcoholics, whereas OPRL1 mRNA levels were decreased (1.4-fold) in the central amygdala. No changes in expression of these genes in other brain areas analyzed were evident. We hypothesise that chronic ethanol intake downregulates PNOC and OPRL1 gene expression in the hippocampus and amygdala, respectively. The findings may be also interpreted as inherited molecular differences between alcoholics and controls. The PNOC/OPRL1 downregulation may underlie impairment of cognitive control over alcohol seeking in alcoholics. Stimulation of the OPRL1 receptors with synthetic agonists may increase threshold for activation of ethanol-related behaviour by environmental cues, and thus may reduce cue- or stress-primed relapse to ethanol consumption.

  • 48.
    Kuzmin, Alexander
    et al.
    Department of Clinical Neuroscience, Division of Drug Dependence Research, Karolinska Institutet, Stockholm, Sweden.
    Kreek, Mary Jeanne
    Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY, USA.
    Bakalkin, Georgy
    Department of Clinical Neuroscience, Division of Drug Dependence Research, Karolinska Institutet, Stockholm, Sweden.
    Liljequist, Sture
    Department of Clinical Neuroscience, Division of Drug Dependence Research, Karolinska Institutet, Stockholm, Sweden.
    The nociceptin/orphanin FQ receptor agonist Ro 64-6198 reduces alcohol self-administration and prevents relapse-like alcohol drinking2007In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 32, no 4, p. 902-10Article in journal (Refereed)
    Abstract [en]

    Effects of the opioid receptor like-1 (ORL-1) receptor agonist Ro 64-6198 (0.1, 0.3, and 1.0 mg/kg intraperitoneally (i.p.)) on operant ethanol self-administration and activation of self-administration by ethanol deprivation were studied in male Wistar rats. Acute administration of Ro 64-6198 caused a dose-dependent reduction of ethanol self-administration. In comparison, the opioid antagonist naltrexone (0.1, 0.3, and 1.0 mg/kg i.p.) inhibited ethanol self-administration at all doses tested. Ethanol deprivation for 10 days significantly increased ethanol self-administration during the first 2 days after deprivation. Daily pretreatment with Ro 64-6198 (0.3 mg/kg) or naltrexone (0.3 mg/kg) during the last 3 days of ethanol deprivation abolished the deprivation-induced increase in ethanol intake. Thus, stimulation of the ORL-1 receptors by Ro 64-6198 reduced the acute reinforcing effects of ethanol and prevented relapse-like behavior in the ethanol-deprivation model in a similar manner as a blockade of opioid receptors by naltrexone. Ro 64-6198 at 0.1 and 0.3 mg/kg doses did not alter self-administration of 0.2% saccharin solution, indicating an apparent selectivity of this compound in modification of ethanol reward. These findings add further support to the idea that Ro 64-6198 and potentially other synthetic ORL-1 receptor agonists are as effective as naltrexone in blocking the actions of ethanol important for its addictive potential in animal experiments, and therefore may have therapeutic value in the treatment of alcoholism.

  • 49.
    Kuzmin, Alexander
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Liljequist, Sture
    Meis, Jennifer
    Chefer, Vladimir
    Shippenberg, Toni
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Repeated moderate-dose ethanol bouts impair cognitive function in Wistar rats2012In: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 17, no 1, p. 132-140Article in journal (Refereed)
    Abstract [en]

    The effects of repeated, intermittent administration of a moderate dose of ethanol (3.4 g/kg/day × 6 days, intragastrically via gavages) on cognitive function were examined in male Wistar rats. No significant differences in weight gain between the ethanol- and water-treated rats were found. Analysis of physical dependence revealed no signs of spontaneous withdrawal, whereas withdrawal signs exacerbated by Ro15-4513, an inverse benzodiazepine agonist, were apparent 5 hours but not 24 hours after the cessation of ethanol treatment. Spatial learning and memory, as assessed in the Barnes maze, were impaired 3-6 days following the treatment but recovered by the 11th-14th days. Reversal learning, however, was impaired throughout the 2-week observation period. Thus, bouts of moderate-dose ethanol administration transiently impair spatial learning and memory, and promote cognitive inflexibility. The employed ethanol exposure paradigm may provide a model of human cognitive deficits associated with alcohol binge drinking.

  • 50.
    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)
12 1 - 50 of 86
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf