liu.seSearch for publications in DiVA
Change search
Refine search result
12 1 - 50 of 79
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • 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.
    Aoun, E. G.
    et al.
    Brown Univ, RI 02912 USA.
    Jimenez, V. A.
    Oregon Hlth and Sci Univ, OR 97201 USA.
    Vendruscolo, L. F.
    Scripps Res Inst, CA 92037 USA; NIDA, MD 20892 USA.
    Walter, N. A. R.
    Oregon Hlth and Sci Univ, OR 97201 USA.
    Barbier, Estelle
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Ferrulli, A.
    Univ Cattolica Sacro Cuore, Italy.
    Haass-Koffler, C. L.
    Brown Univ, RI 02912 USA; NIAAA, MD 20892 USA; NIDA, MD 20892 USA.
    Darakjian, P.
    Oregon Hlth and Sci Univ, OR 97201 USA.
    Lee, M. R.
    NIAAA, MD 20892 USA; NIDA, MD 20892 USA.
    Addolorato, G.
    Univ Cattolica Sacro Cuore, Italy.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Hitzemann, R.
    Oregon Hlth and Sci Univ, OR 97201 USA.
    Koob, G. F.
    Scripps Res Inst, CA 92037 USA; NIAAA, MD 20852 USA.
    Grant, K. A.
    Oregon Hlth and Sci Univ, OR 97201 USA.
    Leggio, L.
    Brown Univ, RI 02912 USA; NIAAA, MD 20892 USA; NIDA, MD 20892 USA.
    A relationship between the aldosterone-mineralocorticoid receptor pathway and alcohol drinking: preliminary translational findings across rats, monkeys and humans2018In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 23, no 6, p. 1466-1473Article in journal (Refereed)
    Abstract [en]

    Aldosterone regulates electrolyte and fluid homeostasis through binding to the mineralocorticoid receptors (MRs). Previous work provides evidence for a role of aldosterone in alcohol use disorders (AUDs). We tested the hypothesis that high functional activity of the mineralocorticoid endocrine pathway contributes to vulnerability for AUDs. In Study 1, we investigated the relationship between plasma aldosterone levels, ethanol self-administration and the expression of CYP11B2 and MR (NR3C2) genes in the prefrontal cortex area (PFC) and central nucleus of the amygdala (CeA) in monkeys. Aldosterone significantly increased after 6- and 12-month ethanol self-administration. NR3C2 expression in the CeA was negatively correlated to average ethanol intake during the 12 months. In Study 2, we measured Nr3c2 mRNA levels in the PFC and CeA of dependent and nondependent rats and the correlates with ethanol drinking during acute withdrawal. Low Nr3c2 expression levels in the CeA were significantly associated with increased anxiety-like behavior and compulsive-like drinking in dependent rats. In Study 3, the relationship between plasma aldosterone levels, alcohol drinking and craving was investigated in alcohol-dependent patients. Non-abstinent patients had significantly higher aldosterone levels than abstinent patients. Aldosterone levels positively correlated with the number of drinks consumed, craving and anxiety scores. These findings support a relationship between ethanol drinking and the aldosterone/MR pathway in three different species.

  • 2.
    Aronsson, Gunnar
    et al.
    University of Stockholm, Sweden.
    Theorell, Tores
    University of Stockholm, Sweden; Karolinska Institute, Sweden.
    Grape, Tom
    Health Care Centre, Sweden.
    Hammarstrom, Anne
    University of Umeå, Sweden.
    Högstedt, Christer
    Karolinska Institute, Sweden.
    Marteinsdottir, Ina
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Skoog, Ingmar
    University of Gothenburg, Sweden.
    Traskman-Bendz, Lil
    Lund University, Sweden.
    Hall, Charlotte
    Swedish Council Health Technology Assessment, Sweden.
    A systematic review including meta-analysis of work environment and burnout symptoms2017In: BMC Public Health, ISSN 1471-2458, E-ISSN 1471-2458, Vol. 17, article id 264Article, review/survey (Refereed)
    Abstract [en]

    Background: Practitioners and decision makers in the medical and insurance systems need knowledge on the relationship between work exposures and burnout. Many burnout studies -original as well as reviews-restricted their analyses to emotional exhaustion or did not report results on cynicism, personal accomplishment or global burnout. To meet this need we carried out this review and meta-analyses with the aim to provide systematically graded evidence for associations between working conditions and near-future development of burnout symptoms. Methods: A wide range of work exposure factors was screened. Inclusion criteria were: 1) Study performed in Europe, North America, Australia and New Zealand 1990-2013. 2) Prospective or comparable case control design. 3) Assessments of exposure (work) and outcome at baseline and at least once again during follow up 1-5 years later. Twenty-five articles met the predefined relevance and quality criteria. The GRADE-system with its 4-grade evidence scale was used. Results: Most of the 25 studies focused emotional exhaustion, fewer cynicism and still fewer personal accomplishment. Moderately strong evidence (grade 3) was concluded for the association between job control and reduced emotional exhaustion and between low workplace support and increased emotional exhaustion. Limited evidence (grade 2) was found for the associations between workplace justice, demands, high work load, low reward, low supervisor support, low co-worker support, job insecurity and change in emotional exhaustion. Cynicism was associated with most of these work factors. Reduced personal accomplishment was only associated with low reward. There were few prospective studies with sufficient quality on adverse chemical, biological and physical factors and burnout. Conclusion: While high levels of job support and workplace justice were protective for emotional exhaustion, high demands, low job control, high work load, low reward and job insecurity increased the risk for developing exhaustion. Our approach with a wide range of work exposure factors analysed in relation to the separate dimensions of burnout expanded the knowledge of associations, evidence as well as research needs. The potential of organizational interventions is illustrated by the findings that burnout symptoms are strongly influenced by structural factors such as job demands, support and the possibility to exert control.

  • 3.
    Augier, Eric
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Barbier, Estelle
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Dulman, Russell S
    Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois, Chicago, IL 60612, USA.
    Licheri, Valentina
    Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Göteborg, 413 90 Göteborg, Sweden.
    Augier, Gaëlle
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Domi, Esi
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Barchiesi, Riccardo
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Farris, Sean
    The Waggoner Center for Alcohol and Addiction Research, University of Texas, Austin, TX 78712, USA.
    Nätt, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Mayfield, R Dayne
    The Waggoner Center for Alcohol and Addiction Research, University of Texas, Austin, TX 78712, USA.
    Adermark, Louise
    Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Göteborg, 413 90 Göteborg, Sweden.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    A molecular mechanism for choosing alcohol over an alternative reward.2018In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 360, no 6395, p. 1321-1326Article in journal (Refereed)
    Abstract [en]

    Alcohol addiction leads to increased choice of alcohol over healthy rewards. We established an exclusive choice procedure in which ~15% of outbred rats chose alcohol over a high-value reward. These animals displayed addiction-like traits, including high motivation to obtain alcohol and pursuit of this drug despite adverse consequences. Expression of the γ-aminobutyric acid (GABA) transporter GAT-3 was selectively decreased within the amygdala of alcohol-choosing rats, whereas a knockdown of this transcript reversed choice preference of rats that originally chose a sweet solution over alcohol. GAT-3 expression was selectively decreased in the central amygdala of alcohol-dependent people compared to those who died of unrelated causes. Impaired GABA clearance within the amygdala contributes to alcohol addiction, appears to translate between species, and may offer targets for new pharmacotherapies for treating this disorder.

  • 4.
    Augier, Eric
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Dulman, Russell S.
    NIAAA, MD USA.
    Damadzic, Ruslan
    NIAAA, MD USA.
    Pilling, Andrew
    NIAAA, MD USA.
    Hamilton, Paul
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    The GABA(B) Positive Allosteric Modulator ADX71441 Attenuates Alcohol Self-Administration and Relapse to Alcohol Seeking in Rats2017In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 42, no 9, p. 1789-1799Article in journal (Refereed)
    Abstract [en]

    GABAergic signaling is involved in modulating the reinforcing properties of alcohol, and GABA(B) receptors have been proposed as a potential target for clinical treatment of alcoholism. The orthosteric GABA(B) receptor agonist baclofen has been shown to suppress operant self-administration of alcohol in animals and alcohol use in alcohol-dependent patients, but its utility is limited by a narrow therapeutic index. We tested the effects of ADX71441, a novel GABA(B) receptor positive allosteric modulator, on alcohol-related behaviors in rats. We first assessed the effects of ADX71441 ( 1, 3, 10 and 30 mg/kg, I.P.) on both non-dependent and dependent male Wistar rats trained to self-administer 20% alcohol. We then determined the effects of ADX71441 on stress-induced as well as cue-induced relapse-like behavior. Finally, we sought to identify the brain regions through which ADX71441 may act to prevent relapse-like behavior by mapping the neuronal activation induced by stress-induced reinstatement of alcohol-seeking using c-Fos immunohistochemistry. ADX71441 dose-dependently decreased alcohol self-administration of both dependent and non-dependent animals, but its potency was higher in alcohol-dependent rats. Furthermore, both cue-and stress-induced alcohol seeking were blocked by the GABA(B) receptor positive allosteric modulator. Finally, pretreatment with 3 mg/kg of ADX71441 before stress-induced reinstatement significantly decreased c-Fos expression in a network of brain regions implicated in stress-induced relapse, comprising the nucleus accumbens shell, the dorsal raphe nucleus and the medial prefrontal cortex. Our findings support a causal role of GABAB receptors in alcohol reinforcement and relapse to alcohol seeking. These effects are observed in the absence of significant sedative side effects. Jointly, these observations indicate that GABAB receptor positive allosteric modulators merit being tested clinically for the treatment of alcoholism. Our data also point to a potential biomarker of target engagement for early clinical studies.

  • 5.
    Augier, Eric
    et al.
    Linköping University, Center for Social and Affective Neuroscience (CSAN). Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Dulman, Russell S.
    NIAAA, MD USA.
    Rauffenbart, Caroline
    NIAAA, MD USA.
    Augier, Gaelle
    Linköping University, Center for Social and Affective Neuroscience (CSAN). Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Cross, Alan J.
    AstraZeneca Neurosci, MA USA.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Social and Affective Neuroscience (CSAN). Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    The mGluR2 Positive Allosteric Modulator, AZD8529, and Cue-Induced Relapse to Alcohol Seeking in Rats2016In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 41, no 12, p. 2932-2940Article in journal (Refereed)
    Abstract [en]

    Group II metabotropic glutamate receptors (mGluR2 and mGluR3) may control relapse of alcohol seeking, but previously available Group II agonists were unable to discriminate between mGluR2 and mGluR3. Here we use AZD8529, a novel positive allosteric mGluR2 modulator, to determine the role of this receptor for alcohol-related behaviors in rats. We assessed the effects of AZD8529 (20 and 40 mg/kg s.c.) on male Wistar rats trained to self-administer 20% alcohol and determined the effects of AZD8529 on self-administration, as well as stress-induced and cue-induced reinstatement of alcohol seeking. The on-target nature of findings was evaluated in Indiana P-rats, a line recently shown to carry a mutation that disrupts the gene encoding mGluR2. The behavioral specificity of AZD8529 was assessed using self-administration of 0.2% saccharin and locomotor activity tests. AZD8529 marginally decreased alcohol self-administration at doses that neither affected 0.2% saccharin self-administration nor locomotor activity. More importantly, cue- but not stress-induced alcohol seeking was blocked by the mGluR2 positive allosteric modulator. This effect of AZD8529 was completely absent in P rats lacking functional mGluR2s, demonstrating the receptor specificity of this effect. Our findings provide evidence fora causal role of mGluR2 in cue induced relapse to alcohol seeking. They contribute support for the notion that positive allosteric modulators of mGluR2 block relapse-like behavior across different drug categories.

  • 6.
    Augier, Eric
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Dulman, Russell S.
    National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, USA.
    Singley, Erick
    National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, USA.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    A Method for Evaluating the Reinforcing Properties of Ethanol in Rats without Water Deprivation, Saccharin Fading or Extended Access Training2017In: Journal of Visualized Experiments, ISSN 1940-087X, E-ISSN 1940-087X, no 119, article id e53305Article in journal (Refereed)
    Abstract [en]

    Operant oral self-administration methods are commonly used to study the reinforcing properties of ethanol in animals. However, the standard methods require saccharin/sucrose fading, water deprivation and/or extended training to initiate operant responding in rats. This paper describes a novel and efficient method to quickly initiate operant responding for ethanol that is convenient for experimenters and does not require water deprivation or saccharin/sucrose fading, thus eliminating the potential confound of using sweeteners in ethanol operant self-administration studies. With this method, Wistar rats typically acquire and maintain self-administration of a 20% ethanol solution in less than two weeks of training. Furthermore, blood ethanol concentrations and rewards are positively correlated for a 30 min self-administration session. Moreover, naltrexone, an FDA-approved medication for alcohol dependence that has been shown to suppress ethanol self-administration in rodents, dose-dependently decreases alcohol intake and motivation to consume alcohol for rats self-administering 20% ethanol, thus validating the use of this new method to study the reinforcing properties of alcohol in rats.

  • 7.
    Aziz, Abdul Maruf Asif
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Brothers, Shaun
    University of Miami Health System, University of Miami, Miami, USA.
    Sartor, Gregory
    University of Miami Health System, University of Miami, Miami, USA.
    Holm, Lovisa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Social and Affective Neuroscience (CSAN). Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Wahlestedt, Claes
    University of Miami Health System, University of Miami, Miami, USA.
    Thorsell, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    The nociceptin/orphanin FQ receptor agonist SR-8993 as a candidate therapeutic for alcohol use disorders: validation in rat models2016In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, no 19-20, p. 3553-3563Article in journal (Refereed)
    Abstract [en]

    RATIONALE: Alcoholism is a complex disorder in which diverse pathophysiological processes contribute to initiation and progression, resulting in a high degree of heterogeneity among patients. Few pharmacotherapies are presently available, and patient responses to these are variable. The nociceptin/orphanin FQ (NOP) receptor has been suggested to play a role both in alcohol reward and in negatively reinforced alcohol seeking. Previous studies have shown that NOP-receptor activation reduces alcohol intake in genetically selected alcohol-preferring as well as alcohol-dependent rats. NOP activation also blocks stress- and cue-induced reinstatement of alcohol-seeking behavior.

    OBJECTIVES: Here, we aimed to examine a novel, potent, and brain-penetrant small-molecule NOP-receptor agonist, SR-8993, in animal models of alcohol- as well as anxiety-related behavior using male Wistar rats.

    RESULTS: SR-8993 was mildly anxiolytic when given to naïve animals and potently reversed acute alcohol withdrawal-induced ("hangover") anxiety. SR-8993 reduced both home-cage limited access drinking, operant responding for alcohol, and escalation induced through prolonged intermittent access to alcohol. SR-8993 further attenuated stress- as well as cue-induced relapse to alcohol seeking. For the effective dose (1.0 mg/kg), non-specific effects such as sedation may be limited, since a range of control behaviors were unaffected, and this dose did not interact with alcohol elimination.

    CONCLUSION: These findings provide further support for NOP-receptor agonism as a promising candidate treatment for alcoholism and establish SR-8993 or related molecules as suitable for further development as therapeutics.

  • 8.
    Badiani, Aldo
    et al.
    Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy; Sussex Addiction Research and Intervention Centre (SARIC), University of Sussex, Brighton, UK.
    Berridge, Kent C.
    Department of Psychology, University of Michigan, Ann Arbor, MI, USA.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Nutt, David J.
    Imperial College, London, UK.
    Robinson, Terry E.
    Department of Psychology, University of Michigan, Ann Arbor, MI, USA.
    Comments: Addiction research and theory: a commentary on the Surgeon Generals Report on alcohol, drugs, and health2018In: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 23, no 1, p. 3-5Article in journal (Other academic)
    Abstract [en]

    The Office of the Surgeon General recently produced its first Report on the consequences of alcohol and drug abuse on health, making several very laudable policy recommendations. The Report also emphasizes the importance of adequate funding for biomedical research, which is good news for both researchers and patients. However, the Report is marred by a biased viewpoint on the psychology and neurobiology of drug addiction. We highlight here four controversial issues that were depicted as facts in the Report, thereby potentially misleading non-expert readers about the current state-of-the-art understanding of the psychology and neurobiology of drug addiction. It will be important to recognize a fuller range of scientific viewpoints in addiction neuroscience to avoid amplifying this bias in the coming years.

  • 9.
    Baker, Maggie
    et al.
    NIAAA, USA.
    Lindell, Stephen G.
    NIAAA, USA.
    Driscoll, Carlos A.
    NIAAA, USA.
    Zhou, Zhifeng
    NIAAA, USA.
    Yuan, Qiaoping
    NIAAA, USA.
    Schwandt, Melanie L.
    NIAAA, USA.
    Miller-Crews, Isaac
    NIAAA, USA.
    Simpson, Elizabeth A.
    Eunice Shriver Kennedy National Institute Child Health and Huma, MD 20837 USA.
    Paukner, Annika
    Eunice Shriver Kennedy National Institute Child Health and Huma, MD 20837 USA.
    Francesco Ferrari, Pier
    University of Claude Bernard Lyon, France.
    Kumar Sindhu, Ravi
    NIAAA, MD 20852 USA.
    Razaqyar, Muslima
    NIAAA, USA.
    Sommer, Wolfgang H.
    Heidelberg University, Germany; Heidelberg University, Germany.
    Lopez, Juan F.
    University of Michigan, MI 48109 USA.
    Thompson, Robert C.
    University of Michigan, MI 48109 USA.
    Goldman, David
    NIAAA, USA.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Dee Higley, J.
    Brigham Young University, UT 84602 USA.
    Suomi, Stephen J.
    Eunice Shriver Kennedy National Institute Child Health and Huma, MD 20837 USA.
    Barr, Christina S.
    NIAAA, USA.
    Early rearing history influences oxytocin receptor epigenetic regulation in rhesus macaques2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 44, p. 11769-11774Article in journal (Refereed)
    Abstract [en]

    Adaptations to stress can occur through epigenetic processes and may be a conduit for informing offspring of environmental challenge. We employed ChIP-sequencing for H3K4me3 to examine effects of early maternal deprivation (peer-rearing, PR) in archived rhesus macaque hippocampal samples (male, n = 13). Focusing on genes with roles in stress response and behavior, we assessed the effects of rearing on H3K4me3 binding by ANOVA. We found decreased H3K4me3 binding at genes critical to behavioral stress response, the most robust being the oxytocin receptor gene OXTR, for which we observed a corresponding decrease in RNA expression. Based on this finding, we performed behavioral analyses to deter mine whether a gain-of-function nonsynonymous OXTR SNP inter acted with early stress to influence relevant behavioral stress reactivity phenotypes (n = 194), revealing that this SNP partially rescued the PR phenotype. PR infants exhibited higher levels of separation anxiety and arousal in response to social separation, but infants carrying the alternative OXTR allele did not exhibit as great a separation response. These data indicate that the oxytocin system is involved in social-separation response and suggest that epigenetic down-modulation of OXTR could contribute to behavior al differences observed in PR animals. Epigenetic changes at OXTR may represent predictive adaptive responses that could impart readiness to respond to environmental challenge or maintain proximity to a caregiver but also contribute to behavioral pathology. Our data also demonstrate that OXTR polymorphism can permit animals to partially overcome the detrimental effects of early maternal deprivation, which could have translational implications for human psychiatric disorders.

  • 10.
    Barbier, Estelle
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    mTORC and ProSAPiP1: How Alcohol Changes Synapses of Reward Circuitry2017In: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 96, no 1Article in journal (Other academic)
    Abstract [en]

    Alcohol addiction is characterized by broad and persistent changes in brain function, but the underlying neural adaptations remain largely unknown. In this issue of Neuron, Laguesse et al. (2017) describe a neural mechanism through which long-term alcohol exposure induces structural and synaptic adaptations that promote excessive alcohol use.

  • 11.
    Barbier, Estelle
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Johnstone, A. L.
    University of Miami, FL 33136 USA.
    Khomtchouk, B. B.
    University of Miami, FL 33136 USA.
    Tapocik, J. D.
    NIAAA, MD USA.
    Pitcairn, C.
    NIAAA, MD USA.
    Rehman, F.
    NIAAA, MD USA.
    Augier, Eric
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Borich, A.
    NIAAA, MD USA.
    Schank, J. R.
    University of Georgia, GA 30602 USA.
    Rienas, C. A.
    University of Miami, FL 33136 USA.
    Van Booven, D. J.
    University of Miami, FL 33136 USA.
    Sun, H.
    NIAAA, MD USA.
    Nätt, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Wahlestedt, C.
    University of Miami, FL 33136 USA; University of Miami, FL 33136 USA.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry. NIAAA, MD USA.
    Dependence-induced increase of alcohol self-administration and compulsive drinking mediated by the histone methyltransferase PRDM22017In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 22, no 12, p. 1746-1758Article in journal (Refereed)
    Abstract [en]

    Epigenetic processes have been implicated in the pathophysiology of alcohol dependence, but the specific molecular mechanisms mediating dependence-induced neuroadaptations remain largely unknown. Here, we found that a history of alcohol dependence persistently decreased the expression of Prdm2, a histone methyltransferase that monomethylates histone 3 at the lysine 9 residue (H3K9me1), in the rat dorsomedial prefrontal cortex (dmPFC). Downregulation of Prdm2 was associated with decreased H3K9me1, supporting that changes in Prdm2 mRNA levels affected its activity. Chromatin immunoprecipitation followed by massively parallel DNA sequencing showed that genes involved in synaptic communication are epigenetically regulated by H3K9me1 in dependent rats. In non-dependent rats, viral-vector-mediated knockdown of Prdm2 in the dmPFC resulted in expression changes similar to those observed following a history of alcohol dependence. Prdm2 knockdown resulted in increased alcohol self-administration, increased aversion-resistant alcohol intake and enhanced stress-induced relapse to alcohol seeking, a phenocopy of postdependent rats. Collectively, these results identify a novel epigenetic mechanism that contributes to the development of alcohol-seeking behavior following a history of dependence.

  • 12.
    Barbier, Estelle
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Tapocik, Jenica D.
    NIAAA, MD 20892 USA.
    Juergens, Nathan
    NIAAA, MD 20892 USA.
    Pitcairn, Caleb
    NIAAA, MD 20892 USA.
    Borich, Abbey
    NIAAA, MD 20892 USA.
    Schank, Jesse R.
    NIAAA, MD 20892 USA.
    Sun, Hui
    NIAAA, MD 20892 USA.
    Schuebel, Kornel
    NIAAA, MD 20892 USA.
    Zhou, Zhifeng
    NIAAA, MD 20892 USA.
    Yuan, Qiaoping
    NIAAA, MD 20892 USA.
    Vendruscolo, Leandro F.
    NIDA, MD 21224 USA.
    Goldman, David
    NIAAA, MD 20892 USA.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    DNA Methylation in the Medial Prefrontal Cortex Regulates Alcohol-Induced Behavior and Plasticity2015In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 35, no 15, p. 6153-6164Article in journal (Refereed)
    Abstract [en]

    Recent studies have suggested an association between alcoholism and DNA methylation, a mechanism that can mediate long-lasting changes in gene transcription. Here, we examined the contribution of DNA methylation to the long-term behavioral and molecular changes induced by a history of alcohol dependence. In search of mechanisms underlying persistent rather than acute dependence-induced neuroadaptations, we studied the role of DNA methylation regulating medial prefrontal cortex (mPFC) gene expression and alcohol-related behaviors in rats 3 weeks into abstinence following alcohol dependence. Postdependent rats showed escalated alcohol intake, which was associated with increased DNA methylation as well as decreased expression of genes encoding synaptic proteins involved in neurotransmitter release in the mPFC. Infusion of the DNA methyltransferase inhibitor RG108 prevented both escalation of alcohol consumption and dependence-induced downregulation of 4 of the 7 transcripts modified in postdependent rats. Specifically, RG108 treatment directly reversed both downregulation of synaptotagmin 2 (Syt2) gene expression and hypermethylation on CpG#5 of its first exon. Lentiviral inhibition of Syt2 expression in the mPFC increased aversion-resistant alcohol drinking, supporting a mechanistic role of Syt2 in compulsive-like behavior. Our findings identified a functional role of DNA methylation in alcohol dependence-like behavioral phenotypes and a candidate gene network that may mediate its effects. Together, these data provide novel evidence for DNA methyltransferases as potential therapeutic targets in alcoholism.

  • 13.
    Bay-Richter, Cecilie
    et al.
    Aarhus University, Denmark.
    Linderholm, Klas R.
    Karolinska Institute, Sweden.
    Lim, Chai K.
    Macquarie University, Australia.
    Samuelsson, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry. Linköping University, Faculty of Medicine and Health Sciences.
    Traskman-Bendz, Lil
    Lund University, Sweden.
    Guillemin, Gilles J.
    Macquarie University, Australia.
    Erhardt, Sophie
    Karolinska Institute, Sweden.
    Brundin, Lena
    Michigan State University, MI USA; Van Andel Research Institute, MI USA.
    A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate receptor in depression and suicidality2015In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 43, p. 110-117Article in journal (Refereed)
    Abstract [en]

    Background: Patients with depression and suicidality suffer from low-grade neuroinflammation. Proinflammatory cytokines activate indoleamine 2,3-dioxygenase, an initial enzyme of the kynurenine pathway. This pathway produces neuroactive metabolites, including quinolinic- and kynurenic acid, binding to the glutamate N-methyl-D-aspartate-receptor, which is hypothesized to be part of the neural mechanisms underlying symptoms of depression. We therefore hypothesized that symptoms of depression and suicidality would fluctuate over time in patients prone to suicidal behavior, depending on the degree of inflammation and kynurenine metabolite levels in the cerebrospinal fluid (CSF). Methods: We measured cytokines and kynurenine metabolites in CSF, collected from suicide attempters at repeated occasions over 2 years (total patient samples n = 143, individuals n = 30) and healthy controls (n = 36). The association between the markers and psychiatric symptoms was assessed using the Montgomery Asberg Depression Rating Scale and the Suicide Assessment Scale. Results: Quinolinic acid was increased and kynurenic acid decreased over time in suicidal patients versus healthy controls. Furthermore, we found a significant association between low kynurenic acid and severe depressive symptoms, as well as between high interleukin-6 levels and more severe suicidal symptoms. Conclusions: We demonstrate a long-term dysregulation of the kynurenine pathway in the central nervous system of suicide attempters. An increased load of inflammatory cytokines was coupled to more severe symptoms. We therefore suggest that patients with a dysregulated kynurenine pathway are vulnerable to develop depressive symptoms upon inflammatory conditions, as a result the excess production of the NMDA-receptor agonist quinolinic acid. This study provides a neurobiological framework supporting the use of NMDA-receptor antagonists in the treatment of suicidality and depression. (C) 2014 Elsevier Inc. All rights reserved.

  • 14.
    Bejerot, Susanne
    et al.
    Karolinska Institutet, Clinical Neuroscience Stockholm, Sweden .
    Landén, Mikael
    Göteborgs universitet, Sahlgrenska akademin, Sweden.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Anckarsäter, Henrik
    Göteborgs universitet, Sahlgrenska akademin, Sweden.
    Waern, Magda
    Göteborgs universitet, Sahlgrenska akademin, Sweden.
    Socialstyrelsens målnivåer signalerar brist på tillit in Lakartidningen, vol 114, issue , pp2017In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 114Article in journal (Other academic)
  • 15.
    Bendix, Marie
    et al.
    Department of Consultation Psychiatry, Psychiatry Southwest, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Wahlstrom, Lars
    Department of Consultation Psychiatry, Psychiatry Southwest, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    John, Michael
    Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Lexne, Erik
    Färjestaden Health Care Centre, Sweden.
    Konig, Monika
    PBO Globen, Stockholm, Sweden.
    Ostryd, Pia
    Region Östergötland.
    Issursing, Abha
    Department of Psychiatry, Uppsala University Hospital, Sweden.
    Strindhall, Par
    Department of Psychiatry, Ryhov Hospital, Jönköping, Sweden.
    Letter: Towards a Swedish identity in consultation-liaison (CL) psychiatry and psychosomatics - Re-foundation of the Swedish Association of CL Psychiatry in JOURNAL OF PSYCHOSOMATIC RESEARCH, vol 108, issue , pp 20-212018In: Journal of Psychosomatic Research, ISSN 0022-3999, E-ISSN 1879-1360, Vol. 108, p. 20-21Article in journal (Other academic)
    Abstract [en]

    n/a

  • 16.
    Bernardi, R. E.
    et al.
    Heidelberg University, Germany.
    Zohsel, K.
    Heidelberg University, Germany.
    Hirth, N.
    Heidelberg University, Germany.
    Treutlein, J.
    Heidelberg University, Germany.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Social and Affective Neuroscience (CSAN). Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Laucht, M.
    Heidelberg University, Germany.
    Spanagel, R.
    Heidelberg University, Germany.
    Sommer, W. H.
    Heidelberg University, Germany.
    A gene-by-sex interaction for nicotine reward: evidence from humanized mice and epidemiology2016In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 6, no e861Article in journal (Refereed)
    Abstract [en]

    It has been proposed that vulnerability to nicotine addiction is moderated by variation at the mu-opioid receptor locus (OPRM1), but results from human studies vary and prospective studies based on genotype are lacking. We have developed a humanized mouse model of the most common functional OPRM1 polymorphism rs1799971_A4G (A118G). Here we use this model system together with a cohort of German youth to examine the role of the OPRM1 A118G variation on nicotine reward. Nicotine reinforcement was examined in the humanized mouse model using i.v. self-administration. Male (n = 17) and female (n = 26) mice homozygous either for the major human A allele (AA) or the minor G allele (GG) underwent eight daily 2 h sessions of nicotine self-administration. Furthermore, male (n = 104) and female (n = 118) subjects homozygous for the A allele or carrying the G allele from the Mannheim Study of Children at Risk were evaluated for pleasurable and unpleasant experiences during their initial smoking experience. A significant sex-by-genotype effect was observed for nicotine self-administration. Male 118GG mice demonstrated higher nicotine intake than male 118AA mice, suggesting increased nicotine reinforcement. In contrast, there was no genotype effect in female mice. Human male G allele carriers reported increased pleasurable effects from their first smoking experience, as compared to male homozygous A, female G and female homozygous A allele carriers. The 118G allele appears to confer greater sensitivity to nicotine reinforcement in males, but not females.

  • 17.
    Bilbao, Ainhoa
    et al.
    University of Heidelberg, Mannheim, Germany.
    Robinson, J Elliott
    Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Malanga, C J
    Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
    Spanagel, Rainer
    University of Heidelberg, Mannheim, Germany.
    Sommer, Wolfgang H
    University of Heidelberg, Mannheim, Germany.
    Thorsell, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    A Pharmacogenetic Determinant of Mu-Opioid Receptor Antagonist Effects on Alcohol Reward and Consumption: Evidence from Humanized Mice.2015In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 77, no 10, p. 850-858Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: It has been proposed that therapeutic responses to naltrexone in alcoholism are moderated by variation at the mu-opioid receptor gene locus (OPRM1). This remains controversial because human results vary and no prospectively genotyped studies have been reported. We generated humanized mice carrying the respective human OPRM1 A118G alleles. Here, we used this model system to examine the role of OPRM1 A118G variation for opioid antagonist effects on alcohol responses.

    METHODS: Effects of naltrexone on alcohol reward were examined using intracranial self-stimulation. Effects of naltrexone or nalmefene on alcohol intake were examined in continuous access home cage two-bottle free-choice drinking and operant alcohol self-administration paradigms.

    RESULTS: Alcohol lowered brain stimulation reward thresholds in 118GG mice in a manner characteristic of rewarding drugs, and this effect was blocked by naltrexone. Brain stimulation reward thresholds were unchanged by alcohol or naltrexone in 118AA mice. In the home cage, increased alcohol intake emerged in 118GG mice with increasing alcohol concentrations and was 33% higher at 17% alcohol. At this concentration, naltrexone selectively suppressed alcohol intake in 118GG animals to a level virtually identical to that of 118AA mice. No effect of naltrexone was found in the latter group. Similarly, both naltrexone and nalmefene were more effective in suppressing operant alcohol self-administration in 118GG mice.

    CONCLUSIONS: In a model that allows close experimental control, OPRM1 A118G variation robustly moderates effects of opioid antagonism on alcohol reward and consumption. These findings strongly support a personalized medicine approach to alcoholism treatment that takes into account OPRM1 genotype.

  • 18.
    Brundin, L.
    et al.
    Van Andel Research Institute, MI 49503 USA.
    Sellgren, C. M.
    Karolinska Institute, Sweden; Broad Institute MIT and Harvard, MA USA; Massachusetts Gen Hospital, MA USA.
    Lim, C. K.
    Macquarie University, Australia.
    Grit, J.
    Van Andel Research Institute, MI 49503 USA.
    Palsson, E.
    Gothenburg University, Sweden.
    Landen, M.
    Gothenburg University, Sweden.
    Samuelsson, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry. Karolinska Institute, Sweden.
    Lundgren, Kristoffer
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Brundin, P.
    Van Andel Research Institute, MI 49503 USA.
    Fuchs, D.
    Medical University of Innsbruck, Austria.
    Postolache, T. T.
    University of Maryland, MD 21201 USA; Rocky Mt MIRECC, CO USA.
    Traskman-Bendz, L.
    Lund University, Sweden.
    Guillemin, G. J.
    Macquarie University, Australia; NHMRC Centre Research Excellence Suicide Prevent CRESP, Australia.
    Erhardt, S.
    Karolinska Institute, Sweden.
    An enzyme in the kynurenine pathway that governs vulnerability to suicidal behavior by regulating excitotoxicity and neuroinflammation2016In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 6, no e865Article in journal (Refereed)
    Abstract [en]

    Emerging evidence suggests that inflammation has a key role in depression and suicidal behavior. The kynurenine pathway is involved in neuroinflammation and regulates glutamate neurotransmission. In the cerebrospinal fluid (CSF) of suicidal patients, levels of inflammatory cytokines and the kynurenine metabolite quinolinic acid (QUIN), an N-methyl-D-aspartate receptor agonist, are increased. The enzyme amino-beta-carboxymuconate-semialdehyde-decarboxylase (ACMSD) limits QUIN formation by competitive production of the neuroprotective metabolite picolinic acid (PIC). Therefore, decreased ACMSD activity can lead to excess QUIN. We tested the hypothesis that deficient ACMSD activity underlies suicidal behavior. We measured PIC and QUIN in CSF and plasma samples from 137 patients exhibiting suicidal behavior and 71 healthy controls. We used DSM-IV and the Montgomery-Asberg Depression Rating Scale and Suicide Assessment Scale to assess behavioral changes. Finally, we genotyped ACMSD tag single nucleotide polymorphisms (SNPs) in 77 of the patients and 150 population-based controls. Suicide attempters had reduced PIC and a decreased PIC/QUIN ratio in both CSF (Pamp;lt;0.001) and blood (P=0.001 and Pamp;lt;0.01, respectively). The reductions of PIC in CSF were sustained over 2 years after the suicide attempt based on repeated measures. The minor C allele of the ACMSD SNP rs2121337 was more prevalent in suicide attempters and associated with increased CSF QUIN. Taken together, our data suggest that increased QUIN levels may result from reduced activity of ACMSD in suicidal subjects. We conclude that measures of kynurenine metabolites can be explored as biomarkers of suicide risk, and that ACMSD is a potential therapeutic target in suicidal behavior.

  • 19.
    Brus, O.
    et al.
    Örebro University, Sweden.
    Cao, Y.
    Örebro University, Sweden; Karolinska Institute, Sweden.
    Gustafsson, E.
    Umeå University Hospital, Sweden.
    Hulten, M.
    Lund University, Sweden.
    Landen, M.
    Karolinska Institute, Sweden; Gothenburg University, Sweden.
    Lundberg, J.
    Karolinska Institute, Sweden; Stockholm County Council, Sweden.
    Nordanskog, Pia
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Nordenskjold, A.
    Örebro University, Sweden.
    Self-assessed remission rates after electroconvulsive therapy of depressive disorders2017In: European psychiatry, ISSN 0924-9338, E-ISSN 1778-3585, Vol. 45, p. 154-160Article in journal (Refereed)
    Abstract [en]

    Background: Electroconvulsive therapy (ECT) effectively treats severe depression, but not all patients remit. The aim of the study was to identify clinical factors that associate with ECT-induced remission in a community setting. Methods: Depressed patients who underwent ECT in 2011-2014 were identified from the Swedish National Quality Register for ECT. Remission was defined as self-rated Montgomery-Asberg Depression Rating Scale scores of 0-10 after ECT. Other registers provided data on previous antidepressant use, comorbidities, and demographics. Results: Of 1671 patients fulfilling the inclusion criteria, 42.8% achieved remission. Older age, education length over 9 years, psychotic symptoms, shorter duration of preceding antidepressant use, pulse width stimulus amp;gt;= 0.50 ms, absence of substance use disorders, anxiety diagnosis, lamotrigine, and benzodiazepines, were associated with remission. Conclusions: This study shows that psychotic subtype of depression and older age are clinically relevant predictors of a beneficial ECT effect. Additionally, ECT outcomes can be further improved by optimizing the treatment technique and concomitant medication. (C) 2017 The Author(s). Published by Elsevier Masson SAS.

  • 20.
    Bäckryd, Emmanuel
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Hoffmann, Mikael
    Stiftelsen NEPI - nätverk för läkmedelsepidemiologi - Linköping, Sweden .
    Dynamiken i förskrivningen av opioider i Sverige 2000–2015 - Markanta omfördelningar inom opioidgruppen, men ingen »epidemi«2017In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 114Article in journal (Refereed)
    Abstract [en]

    Opioid prescription changes in Sweden 2000-2015 In contrast to the well-established »opioid epidemic« in the US, very little is known about how the prescription of opioids in Sweden has developed during the last decade. Aggregated data from the open Statistical database of the Swedish Board of Health and Welfare were analyzed descriptively. The yearly prevalence of opioid prescription did not change 2006-2015, but there were dramatic shifts in the choice of opioids. During this period, dextropropoxyphene was pulled off the market. Tramadol was used by fewer individuals (-54 % over the decade), but dosages expressed as Defined Daily Dose/patient/year (DDD/pat/y) increased (+41 %). In contrast, oxycodone and morphine were used by more individuals (+465 % and +137 %, respectively), but DDD/pat/y decreased during the period (-56% and -54%). Studies on non-aggregated data from available registries are needed to further elucidate the circumstances and possible consequences of these shifts in opioid prescription patterns.

  • 21.
    Chau, David T.
    et al.
    Laureate Institute for Brain Research, Tulsa, Oklahoma, USA.
    Fogelman, Phoebe
    University of Tennessee, Knoxville, Tennessee, USA.
    Nordanskog, Pia
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Drevets, Wayne C.
    Laureate Institute for Brain Research, Tulsa, Oklahoma, USA; Janssen Research and Development, Janssen Pharmaceuticals of Johnson and Johnson, Titusville, New Jersey, USA.
    Hamilton, Paul J.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Laureate Institute for Brain Research, Tulsa, Oklahoma, USA.
    Distinct Neural-Functional Effects of Treatments With Selective Serotonin Reuptake Inhibitors, Electroconvulsive Therapy, and Transcranial Magnetic Stimulation and Their Relations to Regional Brain Function in Major Depression: A Meta-analysis2017In: Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, ISSN 2451-9030, Vol. 2, no 4, p. 318-326Article in journal (Refereed)
    Abstract [en]

    Functional neuroimaging studies have examined the neural substrates of treatments for major depressive disorder (MDD). Low sample size and methodological heterogeneity, however, undermine the generalizability of findings from individual studies. We conducted a meta-analysis to identify reliable neural changes resulting from different modes of treatment for MDD and compared them with each other and with reliable neural functional abnormalities observed in depressed versus control samples.

  • 22.
    Checa, Antonio
    et al.
    Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
    Malmqvist, Anna
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Flyckt, Lena
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet and Stockholm County Council, Stockholm, Sweden.
    Schwieler, Lilly
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Samuelsson, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Skogh, Elisabeth
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Cervenka, Simon
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet and Stockholm County Council, Stockholm, Sweden.
    Dahl, Marja-Liisa
    Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Piehl, Fredrik
    Department of Clinical Neurosciences, Section of Neurology, Karolinska Institutet, Stockholm, Sweden.
    Erhardt, Sophie
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Wheelock, Craig E.
    Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
    Cerebrospinal fluid levels of sphingolipids associate with disease severity in first episode psychosis patients2018In: Schizophrenia Research, ISSN 0920-9964, E-ISSN 1573-2509, Vol. 199, p. 438-441Article in journal (Other academic)
    Abstract [en]

    n/a

  • 23.
    Cortes, Carlos R.
    et al.
    NIAAA, MD 20892 USA.
    Grodin, Erica N.
    NIAAA, MD 20892 USA.
    Mann, Claire L.
    NIAAA, MD 20892 USA.
    Mathur, Karan
    NIAAA, MD 20892 USA.
    Kerich, Michael
    NIAAA, MD 20892 USA.
    Zhu, Xi
    NIAAA, MD 20892 USA.
    Schwandt, Melanie
    NIAAA, MD 20892 USA.
    Diazgranados, Nancy
    NIAAA, MD 20892 USA.
    George, David T.
    NIAAA, MD 20892 USA.
    Momenan, Reza
    NIAAA, MD 20892 USA.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Insula Sensitivity to Unfairness in Alcohol Use Disorder2018In: Alcohol and Alcoholism, ISSN 0735-0414, E-ISSN 1464-3502, Vol. 53, no 3, p. 201-208Article in journal (Refereed)
    Abstract [en]

    Aims: Social decision making has recently been evaluated in alcohol use disorder (AUD) using the ultimatum game (UG) task, suggesting a possible deficit in aversive emotion regulation elicited by the unfairness during this task. Despite the relevance to relapse of this possible faulty regulation, the brain correlates of the UG in AUD are unknown. Methods: In total, 23 AUD and 27 healthy controls (HC) played three consecutive fMRI runs of the UG, while behavioral and brain responses were recorded. Results: Overall, acceptance rate of unfair offers did not differ between groups, but there was a difference in the rate of behavioral change across runs. We found significant anterior insula (aINS) activation in both groups for both fair and unfair conditions, but only HC showed a trend towards increased activation during unfair vs. fair offers. There were not overall whole-brain between-group significant differences. We found a trend of signal attenuation, instead of an increase, in the aINS for AUD when compared to HC during the third run, which is consistent with our recent findings of selective insula atrophy in AUD. Conclusion: We found differential group temporal dynamics of behavioral response in the UG. The HC group had a low acceptance rate for unfair offers in the first two runs that increased markedly for the third run; whereas the AUD group was consistent in their rejection of unfair offers across the three runs. We found a strong significant decrease in neural response across runs for both groups. Short summary: This fMRI study of UG in alcohol use disorder found behavioral group differences in acceptance rate across runs, which together with significant BOLD-signal decrease across runs in UG-related regions in both groups, highlights the impairment of strategy in AUD and the effect of repetitive exposure to unfairness in this task.

  • 24.
    Dahlin, Mats
    et al.
    Psykologpartners, Private Practice, Linköping, Sweden.
    Andersson, Gerhard
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences. Karolinska Institute, Sweden.
    Magnusson, Kristoffer
    Karolinska Institute, Sweden.
    Johansson, Tomas
    Umeå University, Sweden.
    Sjögren, Johan
    Umeå University, Sweden.
    Håkansson, Andreas
    Umeå University, Sweden.
    Pettersson, Magnus
    Umeå University, Sweden.
    Kadowaki, Åsa
    Linköping University, Department of Social and Welfare Studies. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Cuijpers, Pim
    Vrije University of Amsterdam, Netherlands; EMGO Institute Health and Care Research, Netherlands.
    Carlbring, Per
    Stockholm University, Sweden.
    Internet-delivered acceptance-based behaviour therapy for generalized anxiety disorder: A randomized controlled trial2016In: Behaviour Research and Therapy, ISSN 0005-7967, E-ISSN 1873-622X, Vol. 77, p. 86-95Article in journal (Refereed)
    Abstract [en]

    Generalized anxiety disorder (GAD) is a disabling condition which can be treated with cognitive behaviour therapy (CBT). The present study tested the effects of therapist-guided internet-delivered acceptance-based behaviour therapy on symptoms of GAD and quality of life. An audio CD with acceptance and mindfulness exercises and a separate workbook were also included in the treatment. Participants diagnosed with GAD (N = 103) were randomly allocated to immediate therapist-guided internet-delivered acceptance-based behaviour therapy or to a waiting-list control condition. A six month follow-up was also included. Results using hierarchical linear modelling showed moderate to large effects on symptoms of GAD (Cohens d = 0.70 to 0.98), moderate effects on depressive symptoms (Cohens d = 0.51 to 0.56), and no effect on quality of life. Follow-up data showed maintained effects. While there was a 20% dropout rate, sensitivity analyses showed that dropouts did not differ in their degree of change during treatment. To conclude, our study suggests that internet-delivered acceptance based behaviour therapy can be effective in reducing the symptoms of GAD. (C) 2015 Elsevier Ltd. All rights reserved.

  • 25.
    Domi, Esi
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Barbier, Estelle
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Augier, Eric
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Augier, Gaëlle
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Gehlert, D.
    Cerecor, MD USA; Matrix Pharmaceut Consulting, CO USA.
    Barchiesi, Riccardo
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Thorsell, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Holm, Lovisa
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Preclinical evaluation of the kappa-opioid receptor antagonist CERC-501 as a candidate therapeutic for alcohol use disorders2018In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 43, no 9, p. 1805-1812Article in journal (Refereed)
    Abstract [en]

    Prior work suggests a role of kappa-opioid signaling in the control of alcohol drinking, in particular when drinking is escalated due to alcohol-induced long-term neuroadaptations. Here, we examined the small molecule selective kappa antagonist CERC-501 in rat models of alcohol-related behaviors, with the objective to evaluate its potential as a candidate therapeutic for alcohol use disorders. We first tested the effect of CERC-501 on acute alcohol withdrawal-induced anxiety-like behavior. CERC-501 was then tested on basal as well as escalated alcohol self-administration induced by 20% alcohol intermittent access. Finally, we determined the effects of CERC-501 on relapse to alcohol seeking triggered by both stress and alcohol-associated cues. Control experiments were performed to confirm the specificity of CERC-501 effects on alcohol-related behaviors. CERC-501 reversed anxiety-like behavior induced by alcohol withdrawal. It did not affect basal alcohol self-administration but did dose-dependently suppress self-administration that had escalated following long-term intermittent access to alcohol. CERC-501 blocked relapse to alcohol seeking induced by stress, but not when relapse-like behavior was triggered by alcohol-associated cues. The effects of CERC-501 were observed in the absence of sedative side effects and were not due to effects on alcohol metabolism. Thus, in a broad battery of preclinical alcohol models, CERC-501 has an activity profile characteristic of anti-stress compounds. Combined with its demonstrated preclinical and clinical safety profile, these data support clinical development of CERC-501 for alcohol use disorders, in particular for patients with negatively reinforced, stress-driven alcohol seeking and use.

  • 26.
    Domi, Esi
    et al.
    University of Camerino, Italy.
    Uhrig, Stefanie
    Heidelberg University, Germany.
    Soverchia, Laura
    University of Camerino, Italy.
    Spanagel, Rainer
    Heidelberg University, Germany.
    Hansson, Anita C.
    Heidelberg University, Germany.
    Barbier, Estelle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Social and Affective Neuroscience (CSAN). Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Ciccocioppo, Roberto
    University of Camerino, Italy.
    Ubaldi, Massimo
    University of Camerino, Italy.
    Genetic Deletion of Neuronal PPAR gamma Enhances the Emotional Response to Acute Stress and Exacerbates Anxiety: An Effect Reversed by Rescue of Amygdala PPAR gamma Function2016In: JOURNAL OF NEUROSCIENCE, ISSN 0270-6474, Vol. 36, no 50, p. 12611-12623Article in journal (Refereed)
    Abstract [en]

    PPAR gamma is one of the three isoforms of the Peroxisome Proliferator-Activated Receptors (PPARs). PPAR gamma is activated by thiazolidinediones such as pioglitazone and is targeted to treat insulin resistance. PPAR gamma is densely expressed in brain areas involved in regulation of motivational and emotional processes. Here, we investigated the role of PPAR gamma in the brain and explored its role in anxiety and stress responses in mice. The results show that stimulation of PPAR gamma by pioglitazone did not affect basal anxiety, but fully prevented the anxiogenic effect of acute stress. Using mice with genetic ablation of neuronal PPAR gamma (PPAR gamma(NestinCre)), we demonstrated that a lack of receptors, specifically in neurons, exacerbated basal anxiety and enhanced stress sensitivity. The administration of GW9662, a selective PPAR gamma antagonist, elicited a marked anxiogenic response in PPAR gamma wild-type (WT), but not in PPAR gamma(NestinCre) knock-out (KO) mice. Using c-Fos immunohistochemistry, we observed that acute stress exposure resulted in a different pattern of neuronal activation in the amygdala (AMY) and the hippocampus (HIPP) of PPAR gamma(NestinCre) KO mice compared with WT mice. No differences were found between WT and KO mice in hypothalamic regions responsible for hormonal response to stress or in blood corticosterone levels. Microinjection of pioglitazone into the AMY, but not into the HIPP, abolished the anxiogenic response elicited by acute stress. Results also showed that, in both regions, PPAR gamma colocalizes with GABAergic cells. These findings demonstrate that neuronal PPAR gamma is involved the regulation of the stress response and that the AMY is a key substrate for the anxiolytic effect of PPAR gamma

  • 27.
    Elliott Robinson, J.
    et al.
    University of N Carolina, NC 27599 USA; University of N Carolina, NC 27599 USA.
    Vardy, Eyal
    University of N Carolina, NC 27599 USA.
    DiBerto, Jeffrey F.
    University of N Carolina, NC 27599 USA; University of N Carolina, NC 27599 USA.
    Chefer, Vladimir I.
    NIDA, MD USA.
    White, Kate L.
    University of N Carolina, NC 27599 USA.
    Fish, Eric W.
    University of N Carolina, NC 27599 USA.
    Chen, Meng
    University of N Carolina, NC 27599 USA; University of N Carolina, NC 27599 USA.
    Gigante, Eduardo
    NIDA, MD USA.
    Krouse, Michael C.
    University of N Carolina, NC 27599 USA.
    Sun, Hui
    NIAAA, MD USA.
    Thorsell, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Roth, Bryan L.
    University of N Carolina, NC 27599 USA; University of N Carolina, NC 27599 USA.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Malanga, C. J.
    University of N Carolina, NC 27599 USA; University of N Carolina, NC 27599 USA.
    Receptor Reserve Moderates Mesolimbic Responses to Opioids in a Humanized Mouse Model of the OPRM1 A118G Polymorphism2015In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 40, no 11, p. 2614-2622Article in journal (Refereed)
    Abstract [en]

    The OPRM1 A118G polymorphism is the most widely studied mu-opioid receptor (MOR) variant. Although its involvement in acute alcohol effects is well characterized, less is known about the extent to which it alters responses to opioids. Prior work has shown that both electrophysiological and analgesic responses to morphine but not to fentanyl are moderated by OPRM1 A118G variation, but the mechanism behind this dissociation is not known. Here we found that humanized mice carrying the 118GG allele (h/mOPRM1-118GG) were less sensitive than h/mOPRM1-118AA littermates to the rewarding effects of morphine and hydrocodone but not those of other opioids measured with intracranial self-stimulation. Reduced morphine reward in 118GG mice was associated with decreased dopamine release in the nucleus accumbens and reduced effects on GABA release in the ventral tegmental area that were not due to changes in drug potency or efficacy in vitro or receptor-binding affinity. Fewer MOR-binding sites were observed in h/mOPRM1-118GG mice, and pharmacological reduction of MOR availability unmasked genotypic differences in fentanyl sensitivity. These findings suggest that the OPRM1 A118G polymorphism decreases sensitivity to low-potency agonists by decreasing receptor reserve without significantly altering receptor function.

  • 28.
    Emilsson, Maria
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Department of Health Science, Section of Nursing Graduate Level, University West, Trollhättan, Sweden.
    Gustafsson, Per A
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Child and Adolescent Psychiatry in Linköping.
    Öhnström, Gisela
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Child and Adolescent Psychiatry in Linköping.
    Marteinsdottir, Ina
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Beliefs regarding medication and side effects influence treatment adherence in adolescents with attention deficit hyperactivity disorder2017In: European Child and Adolescent Psychiatry, ISSN 1018-8827, E-ISSN 1435-165X, Vol. 26, no 5, p. 559-571Article in journal (Refereed)
    Abstract [en]

    Adherence to attention deficit hyperactivity disorder (ADHD) treatment is important because, when untreated, it may have serious consequences with lifelong effects. In the case of adolescents on long-term medicine prescription, more knowledge is needed regarding adherence and factors influencing adherence, which was the purpose of this study. Adolescents (n = 101) on ADHD medication ≥6 months were administrated questionnaires at a monitoring appointment: Medication Adherence Report Scale (MARS), beliefs about medicines (BMQ) and the Brief Illness Perception Questionnaire (B-IPQ). Adherence was high, the mean value was 88% of the maximum MARS score, and correlated positively with the “BMQ-necessity-concerns differential” but negatively with “BMQ-concerns” and “BMQ-side effects”. Adolescents with more belief in the necessity of the medication, less concerns and less experience of side effects tended to be more adherent to medication prescription (“intentional non-adherence”), while “unintentional non-adherence” (forgetfulness) was associated with how much they perceived that their ADHD affected their lives. In a multiple regression model, the variance of MARS total (R2 = 0.21) and “intentional non-adherence” (R2 = 0.24) was explained by the “BMQ-necessity–concern differential” and “BMQ-experienced side effects”. The variance of “unintentional non-adherence” (R2 = 0.12) was explained by the “BMQ-necessity–concern differential” and “B-IPQ-consequences of ADHD”. In conclusion, adolescents on long-term medication reported good adherence, mainly influenced by more beliefs in the necessity versus concerns of the medications, less experienced side effects and more perceived consequences of ADHD. BMQ could be useful to identify risks of low adherence, which should be counteracted by partially gender-specific interventions.

  • 29.
    Epstein, David H.
    et al.
    NIDA, MD 21224 USA.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Shaham, Yavin
    NIDA, MD 21224 USA.
    Science-Based Actions Can Help Address the Opioid Crisis2018In: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 39, no 11, p. 911-916Article in journal (Other academic)
    Abstract [en]

    The epidemic of addiction and over-dose is real. Addiction among pain patients accounts for only a small proportion but a large number. Scientific opinion leaders can be most effective on two fronts, each relatively low-tech: dissemination and oversight of empirically established treatments, and promulgation of social-science-based strategies for population-level prevention.

  • 30.
    Eriksson, Olle
    et al.
    University of Uppsala Hospital, Sweden.
    Wall, Anders
    University of Uppsala Hospital, Sweden.
    Olsson, Ulf
    Swedish University of Agriculture Science, Sweden.
    Marteinsdottir, Ina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Holstad, Maria
    University of Uppsala Hospital, Sweden.
    Ågren, Hans
    University of Gothenburg, Sweden.
    Hartvig, Per
    University of Copenhagen, Denmark.
    Långström, Bengt
    Uppsala University, Sweden.
    Naessen, Tord
    University of Uppsala Hospital, Sweden.
    Women with Premenstrual Dysphoria Lack the Seemingly Normal Premenstrual Right-Sided Relative Dominance of 5-HTP-Derived Serotonergic Activity in the Dorsolateral Prefrontal Cortices - A Possible Cause of Disabling Mood Symptoms2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 9, article id e0159538Article in journal (Refereed)
    Abstract [en]

    Study Objective To investigate potential quantitative and qualitative differences in brain serotonergic activity between women with Premenstrual Dysphoria (PMD) and asymptomatic controls. Background Serotonin-augmenting drugs alleviate premenstrual mood symptoms in the majority of women with PMD while serotonin-depleting diets worsen PMD symptoms, both indicating intrinsic differences in brain serotonergic activity in women with PMD compared to asymptomatic women. Methods Positron-emission tomography with the immediate precursor of serotonin, 5-hydroxytryptophan (5-HTP), radiolabelled by 11C in the beta-3 position, was performed in the follicular and luteal phases for 12 women with PMD and 8 control women. Brain radioactivity-a proxy for serotonin precursor uptake and synthesis-was measured in 9 regions of interest (ROIs): the right and left sides of the medial prefrontal cortex, dorsolateral prefrontal cortex, putamen and caudate nucleus, and the single "whole brain". Results There were no significant quantitative differences in brain 5-HTP-derived activity between the groups in either of the menstrual phases for any of the 9 ROIs. However, multivariate analysis revealed a significant quantitative and qualitative difference between the groups. Asymptomatic control women showed a premenstrual right sided relative increase in dorsolateral prefrontal cortex 5-HTP derived activity, whereas PMD women displayed the opposite (p = 0.0001). Menstrual phase changes in this asymmetry (premenstrual-follicular) correlated with changes in self ratings of irritability for the entire group (rs = -0.595, p = 0.006). The PMD group showed a strong inverse correlation between phase changes (pre-menstrual-follicular) in plasma levels of estradiol and phase changes in the laterality (dx/sin) of radiotracer activity in the dorsolateral prefrontal ROI (r(s) = -0.635; 0.027). The control group showed no such correlation. Conclusion Absence of increased premenstrual right-sided relative 5-HTP-derived activity of the dorsolateral prefrontal cortices was found to strongly correlate to premenstrual irritability. A causal relationship here seems plausible, and the findings give further support to an underlying frontal brain disturbance in hormonally influenced serotonergic activity in women with PMD. Because of the small number of subjects in the study, these results should be considered preliminary, requiring verification in larger studies.

  • 31.
    Furmark, Tomas
    et al.
    Uppsala University, Sweden.
    Marteinsdottir, Ina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Frick, Andreas
    Uppsala University, Sweden.
    Heurling, Kerstin
    Uppsala University, Sweden.
    Tillfors, Maria
    University of Örebro, Sweden.
    Appel, Lieuwe
    Uppsala University, Sweden.
    Antoni, Gunnar
    Uppsala University, Sweden.
    Hartvig, Per
    University of Copenhagen, Denmark.
    Fischer, Hakan
    Stockholm University, Sweden.
    Langstrom, Bengt
    Uppsala University, Sweden; Southern Denmark University, Denmark.
    Eriksson, Elias
    Gothenburg University, Sweden.
    Fredrikson, Mats
    Uppsala University, Sweden; Karolinska Institute, Sweden.
    Serotonin synthesis rate and the tryptophan hydroxylase-2: G-703T polymorphism in social anxiety disorder2016In: Journal of Psychopharmacology, ISSN 0269-8811, E-ISSN 1461-7285, Vol. 30, no 10, p. 1028-1035Article in journal (Refereed)
    Abstract [en]

    It is disputed whether anxiety disorders, like social anxiety disorder, are characterized by serotonin over- or underactivity. Here, we evaluated whether our recent finding of elevated neural serotonin synthesis rate in patients with social anxiety disorder could be reproduced in a separate cohort, and whether allelic variation in the tryptophan hydroxylase-2 (TPH2) G-703T polymorphism relates to differences in serotonin synthesis assessed with positron emission tomography. Eighteen social anxiety disorder patients and six healthy controls were scanned during 60 minutes in a resting state using positron emission tomography and 5-hydroxy-L-[ -C-11]tryptophan, [C-11]5-HTP, a substrate of the second enzymatic step in serotonin synthesis. Parametric images were generated, using the reference Patlak method, and analysed using Statistical Parametric Mapping (SPM8). Blood samples for genotyping of the TPH2 G-703T polymorphism were obtained from 16 social anxiety disorder patients (T carriers: n=5, GG carriers: n=11). A significantly elevated [C-11]5-HTP accumulation rate, indicative of enhanced decarboxylase activity and thereby serotonin synthesis capacity, was detected in social anxiety disorder patients compared with controls in the hippocampus and basal ganglia nuclei and, at a more lenient (uncorrected) statistical threshold, in the amygdala and anterior cingulate cortex. In patients, the serotonin synthesis rate in the amygdala and anterior cingulate cortex was significantly elevated in TPH2 T carriers in comparison with GG homozygotes. Our results support that social anxiety disorder entails an overactive presynaptic serotonergic system that, in turn, seems functionally influenced by the TPH2 G-703T polymorphism in emotionally relevant brain regions.

  • 32.
    Gowin, Joshua L.
    et al.
    NIAAA, MD USA.
    Vatsalya, Vatsalya
    NIAAA, MD USA; University of Louisville, KY 40292 USA; Robley Rex VAMC, KY USA.
    Westman, Jonathan G.
    NIAAA, MD USA.
    Schwandt, Melanie L.
    NIAAA, MD 20892 USA.
    Bartlett, Selena
    Queensland University of Technology, Australia.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Social and Affective Neuroscience (CSAN). Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Momenan, Reza
    NIAAA, MD USA.
    Ramchandani, Vijay A.
    NIAAA, MD USA.
    The Effect of Varenicline on the Neural Processing of Fearful Faces and the Subjective Effects of Alcohol in Heavy Drinkers2016In: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 40, no 5, p. 979-987Article in journal (Refereed)
    Abstract [en]

    Background: Pharmacotherapies for alcohol use disorder have been shown to reduce hazardous drinking and improve overall health. The effect sizes for the effectiveness of these medications, however, are small, underscoring the need to expand the range of therapeutics and develop personalized treatment approaches. Recent studies have suggested that varenicline, an 42-nicotinic partial agonist widely used for smoking cessation, can help alcoholics reduce drinking, but the neurocognitive underpinnings of its effectiveness remain largely unexplored. Methods: In this double-blind study, 32 heavy drinkers were randomized to receive varenicline (2 mg/d) or placebo. After 2 weeks of dosing, participants underwent functional MRI scans, during which they viewed images of faces with either neutral or fearful expressions at baseline and following an intravenous alcohol infusion to a target breath alcohol concentration of 80 mg%. Blood oxygen level-dependent (BOLD) response was analyzed with Analysis of Functional Neuroimaging software. Linear mixed-effects models were used to examine the effects of facial expression (fearful vs. neutral) and medication (placebo vs. varenicline) on BOLD response. The effect of medication on measures of subjective response to alcohol was also examined. Results: Results indicated a significant facial expression-by-medication interaction in the left amygdala. The groups showed equivalent activation to neutral faces, but, whereas the placebo group showed increased activation to fearful faces, the varenicline group showed no change in activation. Amygdala activation to fearful faces correlated with number of drinks in the previous 90 days and Obsessive Compulsive Drinking Scale scores. There was no effect of varenicline on subjective response to alcohol. Conclusions: Our results indicate that varenicline may disrupt amygdala response to fearful faces in heavy drinkers. Further, amygdala activation correlated with alcohol consumption, suggesting that the effects of varenicline may be related to aspects of drinking behavior. These results suggest that amygdala response to fearful faces may be developed as a biomarker of the effectiveness of medications being developed for the treatment of alcohol use disorder.

  • 33.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Alkohol, droger och hjärnan: tro och vetande utifrån modern neurovetenskap2015Book (Other academic)
    Abstract [sv]

    Alkohol, droger och hjärnan beskriver framsteg inom hjärnforskningen som gjort det möjligt att bättre förstå alkohol- och drogproblem. Boken är skriven från författarens perspektiv som läkare och forskare och visar hur vetenskapens framsteg pekar ut vägar mot empatisk, rationell behandling som alternativ till moraliserande attityder och vårdideologiska strider.

    Missbruksproblem är mycket vanliga, och nästan varje familj har erfarenhet av någon som drabbats. Svenskars användningsmönster av alkohol har förändrats. After Work-ölen och mitt-i-veckan-drinken är förhållandevis nya i svensk dryckeskultur, samtidigt som traditionen av tungt helgdrickande finns kvar. Dessa dryckesbeteenden aktualiserar behovet av fördjupad kunskap och vetenskapligt grundade behandlingsmetoder. För att nå dit behöver forskningens resultat nå ut utanför akademiska kretsar.

  • 34.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Social and Affective Neuroscience (CSAN). Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Substansrelaterade och addiktiva störningar2016In: Psykiatri / [ed] Jörgen Herlofson, Lund: Studentlitteratur, 2016, 2, p. 493-536Chapter in book (Other academic)
    Abstract [en]

    Användning av psykoaktiva substanser (eller "droger") leder till omfattande folkhälsoproblem, men är inte lätt att få in i enkla diagnoskategorier. Det är omdebatterat hurvida substansbruk ska ses som en "sjukdom" och vara en angelägenhet för sjukvården. Vi ska emellertid se att substansbruk ofta uppvisar grundläggande likheter med andra kroniska sjukdomar.

  • 35.
    Heilig, Markus
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Barbier, Estelle
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience.
    Johnstone, A. L.
    University of Miami, FL 33136 USA.
    Tapocik, J.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Meinhardt, M. W.
    Heidelberg University, Germany.
    Pfarr, S.
    Heidelberg University, Germany.
    Wahlestedt, C.
    University of Miami, FL 33136 USA.
    Sommer, W. H.
    Heidelberg University, Germany.
    Reprogramming of mPFC transcriptome and function in alcohol dependence2017In: Genes, Brain and Behavior, ISSN 1601-1848, E-ISSN 1601-183X, Vol. 16, no 1, p. 86-100Article, review/survey (Refereed)
    Abstract [en]

    Despite its limited immediate reinforcement value, alcohol has a potent ability to induce neuroadaptations that promote its incentive salience, escalation of voluntary alcohol intake and aversion-resistant alcohol seeking. A constellation of these traits, collectively called post-dependent, emerges following brain exposure to repeated cycles of intoxication and withdrawal. The medial prefrontal cortex (mPFC) and its subdivisions exert top-down regulation of approach and avoidance behaviors, including those that lead to alcohol intake. Here, we review an emerging literature which indicates that a reprogramming of mPFC function occurs with prolonged exposure of the brain to cycles of alcohol intoxication and withdrawal. This reprogramming results in molecular dysregulations that contribute to the post-dependent syndrome. Convergent evidence has identified neuroadaptations resulting in altered glutamatergic and BDNF-mediated signaling, and for these pathways, direct evidence for a mechanistic role has been obtained. Additional evidence points to a dysregulation of pathways involving calcium homeostasis and neurotransmitter release. Recent findings indicate that global DNA hypermethylation is a key factor in reprogramming the mPFC genome after a history of dependence. As one of the results of this epigenetic remodeling, several histone modifying epigenetic enzymes are repressed. Among these, PR-domain zinc-finger protein 2, a methyltransferase that selectively mono-methylates histone H3 at lysine 9 has been functionally validated to drive several of the molecular and behavioral long-term consequences of alcohol dependence. Information processing within the mPFC involves formation of dynamic neuronal networks, or functional ensembles that are shaped by transcriptional responses. The epigenetic dysregulations identified by our molecular studies are likely to alter this dynamic processing in multiple ways. In summary, epigenetic molecular switches in the mPFC appear to be turned on as alcoholism develops. Strategies to reverse these processes may offer targets for disease-modifying treatments.

  • 36.
    Heilig, Markus
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Social and Affective Neuroscience (CSAN). Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Carlezon, William A.
    Harvard University, MA USA.
    Editorial Material: Circumspectives: Cannabis and Psychiatric Illness: Blunt Thoughts in NEUROPSYCHOPHARMACOLOGY, vol 41, issue 2, pp 391-3922016In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 41, no 2, p. 391-392Article in journal (Other academic)
    Abstract [en]

    n/a

  • 37.
    Heilig, Markus
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Carlezon, William A. Jr.
    Harvard University, MA USA.
    Editorial Material: Circumspectives: The Replacements in NEUROPSYCHOPHARMACOLOGY, vol 40, issue 8, pp 1813-18142015In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 40, no 8, p. 1813-1814Article in journal (Other academic)
    Abstract [en]

    n/a

  • 38.
    Heilig, Markus
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Social and Affective Neuroscience (CSAN). Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Epstein, David H.
    NIDA, MD 21044 USA.
    Nader, Michael A.
    Wake Forest School Med, NC 27157 USA.
    Shaham, Yavin
    NIDA, MD 21044 USA.
    Time to connect: bringing social context into addiction neuroscience2016In: Nature Reviews Neuroscience, ISSN 1471-003X, E-ISSN 1471-0048, Vol. 17, no 9, p. 592-599Article, review/survey (Refereed)
    Abstract [en]

    Research on the neural substrates of drug reward, withdrawal and relapse has yet to be translated into significant advances in the treatment of addiction. One potential reason is that this research has not captured a common feature of human addiction: progressive social exclusion and marginalization. We propose that research aimed at understanding the neural mechanisms that link these processes to drug seeking and drug taking would help to make addiction neuroscience research more clinically relevant.

  • 39.
    Heilig, Markus
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Tagil, Magnus
    Department of Orthopedics, Clinical Sciences, Lund University, Lund, Sweden; Skåne University Hospital, Lund, Sweden.
    Editorial Material: Do we have an opioid crisis in Scandinavia? Time to act? in ACTA ORTHOPAEDICA, vol 89, issue 4, pp 368-3682018In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 89, no 4, p. 368-368Article in journal (Other academic)
    Abstract [en]

    n/a

  • 40.
    Holm, Jonas
    et al.
    Örebro University, Sweden.
    Brus, Ole
    Örebro University, Sweden.
    Bave, Ullvi
    Karolinska Institute, Sweden.
    Landen, Mikael
    Karolinska Institute, Sweden; Gothenburg University, Sweden.
    Lundberg, Johan
    Karolinska Institute, Sweden.
    Nordanskog, Pia
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    von Knorring, Lars
    Uppsala University, Sweden.
    Nordenskjold, Axel
    Örebro University, Sweden.
    Improvement of cycloid psychosis following electroconvulsive therapy2017In: Nordic Journal of Psychiatry, ISSN 0803-9488, E-ISSN 1502-4725, Vol. 71, no 6, p. 405-410Article in journal (Refereed)
    Abstract [en]

    Background: The treatment of choice for cycloid psychosis has traditionally been electroconvulsive therapy (ECT), but there is a lack of studies on its effectiveness.Aims: The primary aim of this register study was to determine the rates of remission and response after ECT for cycloid psychosis. The secondary aim was to examine possible predictors of outcome.Methods: Data were obtained from the National Quality Register for ECT in Sweden. The study population was patients (n=42) who received ECT for acute polymorphic psychotic disorder without symptoms of schizophrenia or for cycloid psychosis between 2011-2015 in 13 hospitals. Remission and response rates were calculated using Clinical Global Impression-Severity (CGI-S) and -Improvement scores, respectively. Variables with possible predictive value were tested using Chi-square and Fishers exact test.Results: The response rate was 90.5%. The remission rate was 45.2%. Of 42 patients, 40 improved their CGI-S score after ECT (pamp;lt;0.001). The mean number of ECT treatments was 2.5 for non-responders and 7.0 for responders (p=0.010). The mean number of ECT treatments did not differ significantly between remitters and non-remitters (7.2 vs 6.1, p=0.31). None of the other investigated potential predictors was statistically significantly associated with outcome.Conclusions: ECT is an effective treatment for cycloid psychosis. Future studies need to compare the outcome of ECT to that of other treatment strategies. Clinical implications: The high response rate with ECT indicates that cycloid psychosis is a clinically useful diagnosis.

  • 41.
    Janelidze, S.
    et al.
    Lund University, Sweden; Lund University, Sweden.
    Suchankova, P.
    University of Gothenburg, Sweden.
    Ekman, A.
    University of Gothenburg, Sweden.
    Erhardt, S.
    Karolinska Institute, Sweden.
    Sellgren, C.
    Karolinska Institute, Sweden.
    Samuelsson, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Westrin, A.
    Lund University, Sweden.
    Minthon, L.
    Lund University, Sweden.
    Hansson, O.
    Lund University, Sweden.
    Traskman-Bendz, L.
    Lund University, Sweden.
    Brundin, L.
    Michigan State University, MI USA; Van Andel Research Institute, MI USA.
    Low IL-8 is associated with anxiety in suicidal patients: genetic variation and decreased protein levels2015In: Acta Psychiatrica Scandinavica, ISSN 0001-690X, E-ISSN 1600-0447, Vol. 131, no 4, p. 269-278Article in journal (Refereed)
    Abstract [en]

    ObjectiveRecent studies indicate that inflammation may play a role in the pathophysiology of suicidality. Interleukin-8 (IL-8) is a chemokine that in addition to its function in the immune system also exert neuroprotective properties. The involvement of this chemokine in neuropsychiatric conditions is incompletely known. MethodWe measured plasma and cerebrospinal fluid (CSF) IL-8, as well as the genotype frequency of a single nucleotide polymorphism (-251A/T, rs4073) in the promoter region of the IL8 gene, in suicide attempters (n=206) and healthy controls (n=578). ResultsPlasma and CSF levels of IL-8 were significantly lower in suicide attempters with anxiety than in healthy controls. IL-8 in both plasma and CSF correlated negatively with symptoms of anxiety. Compared with the population-based cohort, the IL-8-251T allele was more prevalent among female suicide attempters. Furthermore, suicide attempters carrying this allele showed more severe anxiety. This correlative study warrants further mechanistic studies on the effects of IL-8 in the central nervous system. ConclusionWe suggest that IL-8 might be involved in the biological mechanisms mediating resilience to anxiety. Thus, our findings highlight the chemokine IL-8 as a potential target for future development of anti-anxiety treatments and suicide prevention.

  • 42.
    Johansson Capusan, Andrea
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Bendtsen, Preben
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in West Östergötland, Department of Medical Specialist in Motala.
    Marteinsdottir, Ina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Genetic and environmental contributions to the association between attention deficit hyperactivity disorder and alcohol dependence in adulthood: A large population-based twin study.2015In: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, ISSN 1552-4841, E-ISSN 1552-485X, Vol. 168, no 6, p. 414-422Article in journal (Refereed)
    Abstract [en]

    Previous research indicates that attention deficit hyperactivity disorder (ADHD) frequently co-occurs with alcohol dependence; however, the extent to which shared genetic risk factors underpin this association remains unclear. The aim of this study is to investigate the relative importance of genetic, shared, and nonshared environmental factors for the overlap between ADHD and alcohol dependence in adults. Almost 18,000 adult twins aged 20-45 years, from more than 12,000 twin pairs (5,420 complete pairs), from the population-representative Swedish Twin Registry, were included. Self-ratings were used to assess symptoms of ADHD and alcohol dependence. Twin analysis was used to determine the role of additive genetic (A), shared (C), and nonshared environmental (E) factors. As a result, we found a significant association between ADHD and alcohol dependence (odds ratio 3.58; 95% confidence interval, 2.85-4.49). Twin analysis suggested that shared genetic risk factors explained 64% of the overlap between ADHD and alcohol dependence. Nonshared environmental factors accounted for the remaining 36%, whereas the contribution of shared environmental factors was minimal. We found no support for statistically significant sex differences in the overlap between ADHD and alcohol dependence. In conclusion the overlap between ADHD and alcohol dependence in adulthood was largely explained by shared genetic risk factors. This is an important step toward understanding the underlying nature of the risk of alcohol dependence in patients with ADHD and suggests that individuals with ADHD and their family members are important targets for alcohol prevention and treatment.

  • 43.
    Johansson Capusan, Andrea
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Bendtsen, Preben
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in West Östergötland, Department of Medical Specialist in Motala.
    Marteinsdottir, Ina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Larsson, Henrik
    Karolinska Institutet, Stockholm, Sweden.
    Comorbidity of Adult ADHD and Its Subtypes With Substance Use Disorder in a Large Population-Based Epidemiological Study.2016In: Journal of Attention Disorders, ISSN 1087-0547, E-ISSN 1557-1246Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The objective of the study is to explore the role and possible substance preference in ADHD and subtypes in substance use disorder (SUD).

    METHOD: Using self-report data on ADHD Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) symptoms and SUD (alcohol, illicit drugs, and nicotine) in 18,167 Swedish twins, aged 20 to 45 years, we obtained odds ratios (OR) from mixed effect logistic regression, controlling for age, sex, education, and nonindependence of twin data.

    RESULTS: Increased ADHD symptoms were significantly associated with increased odds for all SUD. ORs ranged between 1.33 for regular nicotine (95% confidence interval [CI] = [1.12, 1.59]); 2.54 for multiple drug use (95% CI = [2.00, 3.23]), and 3.58 for alcohol dependence (95% CI = [2.86, 4.49]).

    CONCLUSION: ADHD symptoms and subtypes in the population are associated with increased risks for all SUD outcomes, with no difference between ADHD subtypes, no substance preference, and no sex differences for the comorbidity. Clinicians need to consider ADHD evaluation and treatment as part of management of SUD in adults.

  • 44.
    Johansson Capusan, Andrea
    et al.
    Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine.
    Kuja-Halkola, R.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Bendtsen, Preben
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in West Östergötland, Department of Medical Specialist in Motala.
    Viding, E.
    Developmental Risk and Resilience Unit, University College, London UK.
    McCrory, E.
    Developmental Risk and Resilience Unit, University College, London UK.
    Marteinsdottir, Ina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Larsson, H.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden / Department of Medical Sciences, Örebro University, Örebro, Sweden.
    Childhood maltreatment and attention deficit hyperactivity disorder symptoms in adults: a large twin study2016In: Psychological Medicine, ISSN 0033-2917, E-ISSN 1469-8978, Vol. 46, no 12, p. 2637-2646Article in journal (Refereed)
    Abstract [en]

    Background

    Childhood maltreatment (CM) has been associated with increased risk of attention deficit hyperactivity disorder (ADHD) in children and adults. It is, however, unclear whether this association is causal or due to familial confounding.

    Method

    Data from 18 168 adult twins, aged 20–46 years, were drawn from the population-based Swedish twin registry. Retrospective self-ratings of CM (emotional and physical neglect, physical and sexual abuse and witnessing family violence), and self-ratings for DSM-IV ADHD symptoms in adulthood were analysed. Possible familial confounding was investigated using a within twin-pair design based on monozygotic (MZ) and dizygotic (DZ) twins.

    esults

    CM was significantly associated with increased levels of ADHD symptom scores in adults [regression coefficient: 0.40 standard deviations, 95% confidence interval (CI) 0.37–0.43]. Within twin-pair analyses showed attenuated but significant estimates within DZ (0.29, 95% CI 0.21–0.36) and MZ (0.18, 95% CI 0.10–0.25) twin pairs. Similar results emerged for hyperactive/impulsive and inattentive ADHD symptom scores separately in association with CM. We conducted sensitivity analyses for early maltreatment, before age 7, and for abuse and neglect separately, and found similarly reduced estimates in DZ and MZ pairs. Re-traumatization after age 7 did not significantly influence results.

    Conclusions

    CM was significantly associated with increased ADHD symptoms in adults. Associations were partly due to familial confounding, but also consistent with a causal interpretation. Our findings support cognitive neuroscience studies investigating neural pathways through which exposure to CM may influence ADHD. Clinicians treating adults with ADHD should be aware of the association with maltreatment.

  • 45.
    Johansson Capusan, Andrea
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Yao, S.
    Karolinska Institute, Sweden.
    Kuja-Halkola, R.
    Karolinska Institute, Sweden.
    Bulik, C. M.
    Karolinska Institute, Sweden; University of North Carolina Chapel Hill, NC USA; University of North Carolina Chapel Hill, NC USA.
    Thornton, L. M.
    University of North Carolina Chapel Hill, NC USA.
    Bendtsen, Preben
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in West Östergötland, Department of Medical Specialist in Motala.
    Marteinsdottir, Ina
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Thorsell, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Larsson, H.
    Karolinska Institute, Sweden; Örebro University, Sweden.
    Genetic and environmental aspects in the association between attention-deficit hyperactivity disorder symptoms and binge-eating behavior in adults: a twin study2017In: Psychological Medicine, ISSN 0033-2917, E-ISSN 1469-8978, Vol. 47, no 16, p. 2866-2878Article in journal (Refereed)
    Abstract [en]

    Background Prior research demonstrated that attention-deficit hyperactivity disorder (ADHD) is associated with binge-eating behavior, binge-eating disorder (BED), and bulimia nervosa (BN). The aim of this study was to investigate these associations in an adult twin population, and to determine the extent to which ADHD symptoms and binge-eating behavior share genetic and environmental factors. Methods We used self-reports of current ADHD symptoms and lifetime binge-eating behavior and associated characteristics from a sample of over 18 000 adult twins aged 20-46 years, from the population-based Swedish Twin Registry. Mixed-effects logistic regression was used to examine the association between ADHD and lifetime binge-eating behavior, BED, and BN. Structural equation modeling was used in 13 773 female twins to determine the relative contribution of genetic and environmental factors to the association between ADHD symptoms and binge-eating behavior in female adult twins. Results ADHD symptoms were significantly associated with lifetime binge-eating behavior, BED, and BN. The heritability estimate for current ADHD symptoms was 0.42 [95% confidence interval (CI) 0.41-0.44], and for lifetime binge-eating behavior 0.65 (95% CI 0.54-0.74). The genetic correlation was estimated as 0.35 (95% CI 0.25-0.46) and the covariance between ADHD and binge-eating behavior was primarily explained by genetic factors (91%). Non-shared environmental factors explained the remaining part of the covariance. Conclusions The association between adult ADHD symptoms and binge-eating behavior in females is largely explained by shared genetic risk factors.

  • 46.
    Jönsson, Anna K
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. Natl Board Forens Med, Dept Forens Genet and Forens Chem, Linkoping, Sweden.
    Schill, Johan
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry. Region Jönköping, Sweden.
    Olsson, Hans
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry. Region Jönköping, Sweden.
    Spigset, Olav
    St Olavs Univ Hosp, Norway; Norwegian Univ Sci and Technol, Norway.
    Hägg, Staffan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Venous Thromboembolism During Treatment with Antipsychotics: A Review of Current Evidence2018In: CNS Drugs, ISSN 1172-7047, E-ISSN 1179-1934, Vol. 32, no 1, p. 47-64Article, review/survey (Refereed)
    Abstract [en]

    This article summarises the current evidence on the risk of venous thromboembolism (VTE) with the use of antipsychotics. An increasing number of observational studies indicate an elevated risk of VTE in antipsychotic drug users. Although the use of certain antipsychotics has been associated with VTE, current data can neither conclusively verify differences in occurrence rates of VTE between first- and second-generation antipsychotics or between individual compounds, nor identify which antipsychotic drugs have the lowest risk of VTE. The biological mechanisms involved in the pathogenesis of this adverse drug reaction are still to be clarified but hypotheses such as drug-induced sedation, obesity, increased levels of antiphospholipid antibodies, enhanced platelet aggregation, hyperhomocysteinaemia and hyperprolactinaemia have been suggested. Risk factors associated with the underlying psychiatric disorder may at least partly explain the increased risk. Physicians should be aware of this potentially serious and even sometimes fatal adverse drug reaction and should consider discontinuing or switching the antipsychotic treatment in patients experiencing a VTE. Even though supporting evidence is limited, prophylactic antithrombotic treatment should be considered in risk situations for VTE.

  • 47.
    Kalafateli, Aimilia Lydia
    et al.
    Univ Gothenburg, Sweden.
    Vallof, Daniel
    Univ Gothenburg, Sweden.
    Jornulf, Julia Winsa
    Univ Gothenburg, Sweden.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Jerlhag, Elisabet
    Univ Gothenburg, Sweden.
    A cannabinoid receptor antagonist attenuates ghrelin-induced activation of the mesolimbic dopamine system in mice2018In: Physiology and Behavior, ISSN 0031-9384, E-ISSN 1873-507X, Vol. 184, p. 211-219Article in journal (Refereed)
    Abstract [en]

    Ghrelin has been attributed various physiological processes including food intake and reward regulation, through activation of the mesolimbic dopamine system. Reward modulation involves the mesolimbic dopamine system, consisting of the ventral tegmental area (VTA) dopamine neurons targeting nucleus accumbens (NAc), a system that ghrelin activates through VTA-dependent mechanisms. In the first study, we found that systemic intraperitoneal (ip) administration of rimonabant attenuated intracerebroventricular (icv) ghrelins ability to cause locomotor stimulation and NAc dopamine release in mice. Ghrelin-induced (icv) chow intake was not altered by rimonabant administration (ip). Finally, we showed that bilateral VTA administration of rimonabant blocks the ability of intra-VTA administered ghrelin to increase locomotor activity, but does not affect food intake in mice. Collectively, these data indicate clear dissociation between regulation of food intake and activation of the mesolimbic dopamine system.

  • 48.
    Karlsson, Camilla
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Aziz, Abdul Maruf Asif
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Rehman, Faazal
    NIAAA, MD USA.
    Pitcairn, Caleb
    Laboratory of Clinical and Translational Studies, NIAAA, NIH, Bethesda, Maryland, USA.
    Barchiesi, Riccardo
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Barbier, Estelle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Wendel Hansen, Mikaela
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Gehlert, Don
    CNS Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.
    Steensland, Pia
    Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Social and Affective Neuroscience (CSAN). Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Thorsell, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Melanin-Concentrating Hormone and Its MCH-1 Receptor: Relationship Between Effects on Alcohol and Caloric Intake2016In: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 40, no 10, p. 2199-2207Article in journal (Refereed)
    Abstract [en]

    Background: Reward and energy homeostasis are both regulated by a network of hypothalamic neuropeptide systems. The melanin-concentrating hormone (MCH) and its MCH-1 receptor (MCH1-R) modulate alcohol intake, but it remains unknown to what extent this reflects actions on energy balance or reward. Here, we evaluated the MCH1-R in regulation of caloric intake and motivation to consume alcohol in states of escalated consumption.

    Methods: Rats had intermittent access (IA) to alcohol and were divided into high- and low-drinking groups. Food and alcohol consumption was assessed after administration of an MCH1-R antagonist, GW803430. Next, GW803430 was evaluated on alcohol self-administration in protracted abstinence induced by IA in high-drinking rats. Finally, the effect of GW803430 was assessed on alcohol self-administration in acute withdrawal in rats exposed to alcohol vapor. Gene expression of MCH and MCH1-R was measured in the hypothalamus and nucleus accumbens (NAc) in both acute and protracted abstinence.

    Results: High-drinking IA rats consumed more calories from alcohol than chow and GW803430 decreased both chow and alcohol intake. In low-drinking rats, only food intake was affected. In protracted abstinence from IA, alcohol self-administration was significantly reduced by pretreatment with GW803430 and gene expression of both MCH and the MCH1-R were dysregulated in hypothalamus and NAc. In contrast, during acute withdrawal from vapor exposure, treatment with GW803430 did not affect alcohol self-administration, and no changes in MCH or MCH1-R gene expression were observed.

    Conclusions: Our data suggest a dual role of MCH and the MCH1-R in regulation of alcohol intake, possibly through mechanisms involving caloric intake and reward motivation. A selective suppression of alcohol self-administration during protracted abstinence by GW803430 was observed and accompanied by adaptations in gene expression of MCH and MCH1-R. Selective suppression of escalated consumption renders the MCH1-R an attractive target for treatment of alcohol use disorders.

  • 49.
    Karlsson, Camilla
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Rehman, Faazal
    NIAAA, MD USA.
    Damadzic, Ruslan
    NIAAA, MD USA.
    Atkins, Alison Lynn
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Schank, Jesse R.
    University of Georgia, GA 30602 USA.
    Gehlert, Donald R.
    Lilly Research Labs, IN USA.
    Steensland, Pia
    Karolinska Institute, Sweden.
    Thorsell, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Social and Affective Neuroscience (CSAN). Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Correction: The melanin-concentrating hormone-1 receptor modulates alcohol-induced reward and DARPP-32 phosphorylation (vol 233, nr 12, pp. 2355–2363, 2016)2016In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, no 21-22, p. 3825-3825Article in journal (Other academic)
    Abstract [en]

    n/a

  • 50.
    Karlsson, Camilla
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Rehman, Faazal
    NIH, MD 20892 USA.
    Damdazic, Ruslan
    NIH, MD 20892 USA.
    Atkins, Alison Lynn
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Schank, Jesse R.
    University of Georgia, GA 30602 USA.
    Gehlert, Donald R.
    Eli Lilly and Co, IN 46285 USA.
    Steensland, Pia
    Karolinska Institute, Sweden.
    Thorsell, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Social and Affective Neuroscience (CSAN). Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    The melanin-concentrating hormone-1 receptor modulates alcohol-induced reward and DARPP-32 phosphorylation2016In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, no 12, p. 2355-2363Article in journal (Refereed)
    Abstract [en]

    Melanin-concentrating hormone (MCH) is involved in the regulation of food intake and has recently been associated with alcohol-related behaviors. Blockade of MCH-1 receptors (MCH1-Rs) attenuates operant alcohol self-administration and decreases cue-induced reinstatement, but the mechanism through which the MCH1-R influences these behaviors remains unknown. MCH1-Rs are highly expressed in the nucleus accumbens shell (NAcSh) where they are co-expressed with dopamine (DA) receptors. MCH has been shown to potentiate responses to dopamine and to increase phosphorylation of DARPP-32, an intracellular marker of DA receptor activation, in the NAcSh. In the present study, we investigated the role of the MCH1-R in alcohol reward using the conditioned place preference (CPP) paradigm. We then used immunohistochemistry (IHC) to assess activation of downstream signaling after administration of a rewarding dose of alcohol. We found that alcohol-induced CPP was markedly decreased in mice with a genetic deletion of the MCH1-R as well as after pharmacological treatment with an MCH1-R antagonist, GW803430. In contrast, an isocaloric dose of dextrose did not produce CPP. The increase in DARPP-32 phosphorylation seen in wildtype (WT) mice after acute alcohol administration in the NAcSh was markedly reduced in MCH1-R knock-out (KO) mice. Our results suggest that MCH1-Rs regulate the rewarding properties of alcohol through interactions with signaling cascades downstream of DA receptors in the NAcSh.

12 1 - 50 of 79
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • 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