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  • 1.
    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.

  • 2.
    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.

  • 3.
    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)
  • 4.
    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.

  • 5.
    Björk, Karl
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Terasmaa, Anton
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Sun, Hui
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Sommer, Wolfgang H.
    Central Institute of Mental Health, Mannheim, Germany.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Ethanol-induced activation of AKT and DARPP-32 in the mouse striatum mediated by opioid receptors2010In: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 15, no 3, p. 299-303Article in journal (Refereed)
    Abstract [en]

    The reinforcing properties of ethanol are in part attributed to interactions between opioid and dopaminergic signaling pathways, but intracellular mediators of such interactions are poorly understood. Here we report that an acute ethanol challenge induces a robust phosphorylation of two key signal transduction kinases, AKT and DARPP-32, in the striatum of mice. Ethanol-induced AKT phosphorylation was blocked by the opioid receptor antagonist naltrexone but unaffected by blockade of dopamine D2 receptors via sulpiride. In contrast, DARPP-32 phosphorylation was abolished by both antagonists. These data suggest that ethanol acts via two distinct but potentially synergistic striatal signaling cascades. One of these is D2-dependent, while the other is not. These findings illustrate that pharmacology of ethanol reward is likely more complex than that for other addictive drugs.

  • 6.
    Björk, Karl
    et al.
    Karolinska Institute, Stockholm, Sweden .
    Tronci, Valeria
    Psychobiology Section, NIDA, National Institutes of Health, Baltimore, 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.
    Tanda, Gianluigi
    Psychobiology Section, NIDA, National Institutes of Health, Baltimore, MD, USA .
    Hirth, Natalie
    University of Heidelberg, Mannheim, Germany .
    Heilig, Markus
    Laboratory of Clinical and Translational Studies, NIAAA, National Institutes of Health, Bethesda, MD, USA .
    Hansson, Anita C.
    Laboratory of Clinical and Translational Studies, NIAAA, National Institutes of Health, Bethesda, MD, USA.
    Sommer, Wolfgang H
    Laboratory of Clinical and Translational Studies, NIAAA, National Institutes of Health, Bethesda, MD, USA.
    β-Arrestin 2 knockout mice exhibit sensitized dopamine release and increased reward in response to a low dose of alcohol2013In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 230, no 3, p. 439-449Article in journal (Refereed)
    Abstract [en]

    Rationale

    The rewarding effects of alcohol have been attributed to interactions between opioid and dopaminergic system within the mesolimbic reward pathway. We have previously shown that ablation of β-arrestin 2 (Arrb2), a crucial regulator of μ-opioid receptor function, attenuates alcohol-induced hyperlocomotion and c-fos activation in the nucleus accumbens.

    Objectives

    Here, we further investigated the role of Arrb2 in modulating alcohol-induced dopamine (DA) release and conditioned place preference (CPP). We also assessed the functional importance of Arrb2 for μ-opioid receptor surface expression and signaling following an acute alcohol challenge.

    Methods

    Alcohol-evoked (0.375, 0.75, and 1.5 g/kg intraperitoneally) DA release was measured by in vivo microdialysis in the shell of nucleus accumbens. Reward was assessed by the CPP paradigm. Receptor function was assessed by μ-receptor binding and [35S]GTP-γ-S autoradiography.

    Results

    In Arrb2 knockout mice accumbal DA levels reach maximum response at a lower dose compared to wild-type (wt) animals. In line with these results, Arrb2 knockout mice display increased CPP for alcohol as compared to wt mice. Finally, Arrb2 mutant mice display increased μ-opioid receptor signaling in the ventral and dorsal striatum and amygdala in response to a low dose of alcohol, indicating impaired desensitization mechanisms in these mice.

    Conclusions

    Our results show that Arrb2 modulates the response to low doses of alcohol on various levels including μ-opioid receptor signaling, DA release, and reward. They also reveal a clear dissociation between the effects of Arrb2 on psychomotor and reward behaviors.

  • 7.
    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.

  • 8.
    Ciccocioppo, Roberto
    et al.
    University of Camerino, Italy.
    Gehlert, Donald R.
    Lilly Research Laboratories, Indianapolis, IN, USA.
    Ryabinin, Andrey
    Oregon Health & Science University, Portland, OR, USA.
    Kaur, Simranjit
    Oregon Health & Science University, Portland, OR, USA.
    Cippitelli, Andrea
    University of Camerino, Italy.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Lê, Anh D.
    University of Toronto, Ontario, Canada.
    Hipskind, Philip A.
    Lilly Research Laboratories, Indianapolis, IN, USA.
    Hamdouchi, Chafiq
    Lilly Research Laboratories, Indianapolis, IN, USA.
    Lu, Jianliang
    Lilly Research Laboratories, Indianapolis, IN, USA.
    Hembre, Erik J.
    Lilly Research Laboratories, Indianapolis, IN, USA.
    Cramer, Jeffrey
    Lilly Research Laboratories, Indianapolis, IN, USA.
    Song, Min
    Lilly Research Laboratories, Indianapolis, IN, USA.
    McKinzie, David
    Lilly Research Laboratories, Indianapolis, IN, USA.
    Morin, Michelle
    Lilly Research Laboratories, Indianapolis, IN, USA.
    Economidou, Daina
    University of Camerino, Italy.
    Stopponi, Serena
    University of Camerino, Italy.
    Cannella, Nazzareno
    University of Camerino, Italy.
    Braconi, Simone
    University of Camerino, Italy.
    Kallupi, Marsida
    University of Camerino, Italy.
    de Guglielmo, Giordano
    University of Camerino, Italy.
    Massi, Maurizio
    University of Camerino, Italy.
    George, David T.
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Gilman, Jody
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Hersh, Jacqueline
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Tauscher, Johannes T.
    Lilly Research Laboratories, Indianapolis, IN, USA.
    Hunt, Stephen P.
    University College London, UK.
    Hommer, Daniel
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcolholism, NIH; Bethesda, MD, USA.
    Stress-related neuropeptides and alcoholism: CRH, NPY, and beyond2009In: Alcohol, ISSN 0741-8329, E-ISSN 1873-6823, Vol. 43, no 7, p. 491-498Article in journal (Refereed)
    Abstract [en]

    This article summarizes the proceedings of a symposium held at the conference on "Alcoholism and Stress: A Framework for Future Treatment Strategies" in Volterra, Italy, May 6-9, 2008. Chaired by Markus Heilig and Roberto Ciccocioppo, this symposium offered a forum for the presentation of recent data linking neuropetidergic neurotransmission to the regulation of different alcohol-related behaviors in animals and in humans. Dr. Donald Gehlert described the development of a new corticotrophin-releasing factor receptor 1 antagonist and showed its efficacy in reducing alcohol consumption and stress-induced relapse in different animal models of alcohol abuse. Dr. Andrey Ryabinin reviewed recent findings in his laboratory, indicating a role of the urocortin 1 receptor system in the regulation of alcohol intake. Dr. Annika Thorsell showed data supporting the significance of the neuropeptide Y receptor system in the modulation of behaviors associated with a history of ethanol intoxication. Dr. Roberto Ciccocioppo focused his presentation on the nociceptin/orphanin FQ (N/OFQ) receptors as treatment targets for alcoholism. Finally, Dr. Markus Heilig showed recent preclinical and clinical evidence suggesting that neurokinin 1 antagonism may represent a promising new treatment for alcoholism. Collectively, these investigators highlighted the significance of neuropeptidergic neurotransmission in the regulation of neurobiological mechanisms of alcohol addiction. Data also revealed the importance of these systems as treatment targets for the development of new medication for alcoholism.

  • 9.
    Cippitelli, Andrea
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Damadzic, Ruslan
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Frankola, Kate
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Goldstein, Andrea
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Singley, Erick
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Eskay, Robert L
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Alcohol-induced neurodegeneration, suppression of transforming growth factor-beta, and cognitive impairment in rats: prevention by group II metabotropic glutamate receptor activation2010In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 67, no 9, p. 823-830Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Glutamatergic neurotransmission has been implicated in mechanisms of alcohol-induced neurodegeneration and cognitive impairment, but the underlying mechanism remains unknown. Here, we examined whether the group II metabotropic glutamate receptor agonist LY379268 prevents neuronal death and learning deficits in a rat model of binge-like exposure to alcohol.

    METHODS: Following 4-day binge alcohol exposure concurrent with LY379268 or vehicle treatment, Fluoro-Jade B and transforming growth factor-beta (TGF-beta) staining were carried out, and reversal learning in the Morris water maze was assessed.

    RESULTS: Fluoro-Jade B staining indicating neurodegeneration was most extensive in the ventral hippocampus and the entorhinal cortex (EC). LY379268 was potently neuroprotective in the EC but not in the dentate gyrus of the hippocampus. In parallel, binge alcohol exposure suppressed TGF-beta expression in both the EC and dentate gyrus, whereas LY379268 increased TGF-beta in the EC only. Finally, neuroprotective effects of LY379268 were accompanied by prevention of deficits in spatial reversal learning.

    CONCLUSIONS: Our data support a neuroprotective role for group II metabotropic glutamate receptor agonists and TGF-beta in alcohol-induced neurodegeneration.

  • 10.
    Cippitelli, Andrea
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Damadzic, Ruslan
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Hamelink, Carol
    National Institute of Mental Health, NIH, Bethesda, MD, USA.
    Brunnquell, Michael
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Eskay, Robert L.
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Binge-like ethanol consumption increases corticosterone levels and neurodegneration whereas occupancy of type II glucocorticoid receptors with mifepristone is neuroprotective2014In: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 19, no 1, p. 27-36Article in journal (Refereed)
    Abstract [en]

    Excessive ethanol (EtOH) use leads to impaired memory and cognition. Using a rat model of binge-like intoxication, we tested whether elevated corticosterone (Cort) levels contribute to the neurotoxic consequences of EtOH exposure. Rats were adrenalectomized (Adx) and implanted with cholesterol pellets, or cholesterol pellets containing Cort in order to achieve basal, medium, or high blood concentrations of Cort. Intragastric EtOH or an isocaloric control solution was given three times daily for 4 days to achieve blood alcohol levels ranging between 200 and 350 mg/dl. Mean 24-hour plasma levels of Cort were ∼110 and ∼40 ng/ml in intact EtOH-treated and intact control animals, respectively. Basal Cort replacement concentrations in EtOH-treated Adx animals did not exacerbate alcohol-induced neurodegeneration in the hippocampal dentate gyrus (DG) or the entorhinal cortex (EC) as observed by amino-cupric silver staining. In contrast, Cort replacement pellets resulting in plasma Cort levels twofold higher (medium) than normal, or greater than twofold higher (high) in Adx-Cort-EtOH animals increased neurodegeneration. In separate experiments, pharmacological blockade of the Type II glucocorticoid (GC) receptor was initiated with mifepristone (RU38486; 0, 5, 15 mg/kg/day, i.p.). At the higher dose, mifepristone decreased the number of degenerating hippocampal DG cells in binge-EtOH-treated intact animals, whereas, only a trend for reduction was observed in 15 mg/kg/day mifepristone-treated animals in the EC, as determined by fluoro-jade B staining. These results suggest that elevated circulating Cort in part mediates EtOH-induced neurotoxicity in the brain through activation of Type II GC receptors.

  • 11.
    Cippitelli, Andrea
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Damadzic, Ruslan
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Hansson, Anita C.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Singley, Erick
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Sommer, Wolfgang H.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Eskay, Robert
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Neuropeptide Y (NPY) suppresses yohimbine-induced reinstatement of alcohol seeking2010In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 208, no 3, p. 417-426Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Reinstatement of responding to a previously alcohol-associated lever following extinction is an established model of relapse-like behavior and can be triggered by stress exposure. Here, we examined whether neuropeptide Y (NPY), an endogenous anti-stress mediator, blocks reinstatement of alcohol-seeking induced by the pharmacological stressor yohimbine.

    MATERIALS AND METHODS: NPY [5.0 or 10.0 mug/rat, intracerebroventricularly (ICV)] dose-dependently blocked the reinstatement of alcohol seeking induced by yohimbine (1.25 mg/kg, i.p.) but failed to significantly suppress the maintenance of alcohol self-administration. We then used c-fos expression mapping to examine neuronal activation following treatment with yohimbine or NPY alone or yohimbine following NPY pre-treatment.

    RESULTS AND DISCUSSION: The analysis was focused on a network of structures previously implicated in yohimbine-induced reinstatement, comprised of central (CeA) and basolateral (BLA) amygdala and the shell of the nucleus accumbens (Nc AccS). Within this network, both yohimbine and NPY potently induced neuronal activation, and their effects were additive, presumably indicating activation of excitatory and inhibitory neuronal populations, respectively.

    CONCLUSION: These results suggest that NPY selectively suppresses relapse to alcohol seeking induced by stressful events and support the NPY system as an attractive target for the treatment of alcohol addiction.

  • 12.
    Cippitelli, Andrea
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Damadzic, Ruslan
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Singley, Erick
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Ciccocioppo, Roberto
    University of Camerino, Italy.
    Eskay, Robert L.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Pharmacological blockade of corticotropin-releasing hormone receptor 1 (CRH1R) reduces voluntary consumption of high alcohol concentrations in non-dependent Wistar rats2012In: Pharmacology, Biochemistry and Behavior, ISSN 0091-3057, E-ISSN 1873-5177, Vol. 100, no 3, p. 522-529Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A dysregulation of the corticotropin-releasing hormone (CRH) system has been implicated in the development of excessive alcohol consumption and dependence. The aim of the present study was to evaluate whether the CRH system is also recruited when non-dependent Wistar rats escalate to high alcohol intake in the intermittent (alternate days) model of drinking.

    METHODS: We compared intermittent and continuous access to 20% (v/v) alcohol in a two-bottle free choice drinking paradigm. Following a total of twenty 24-hour exposures for every experimental group, we assessed signs of alcohol withdrawal, including anxiety-like behavior and sensitivity to stress. The selective CRH1 receptor (CRH1R) antagonist antalarmin (0, 10, 20 mg/kg, i.p.) was tested on alcohol consumption.

    RESULTS: Intermittent access to 20% alcohol led non-selected Wistar rats to escalate their voluntary intake to a high and stable level, whereas continuously exposed animals maintained a lower consumption. These groups did not differ in physical withdrawal signs. In addition, no differences were found when anxiogenic-like behavior was studied, neither under basal conditions or following restraint stress. Nevertheless, sensitivity to the treatment with the CRH1R antalarmin was observed since a reduction of 20% alcohol intake was found in both groups of animals regardless of the regimen of alcohol exposure. In addition, antalarmin was effective when injected to animals exposed to intermittent 10% (v/v) alcohol whereas it failed to suppress 10% continuous alcohol intake.

    CONCLUSIONS: Pharmacological blockade of CRH1R reduced alcohol drinking when sustained high levels of intake were achieved suggesting that the CRH system plays a key role when high doses of ethanol are consumed by non-dependent subjects. This supports the notion that CRH system not only maintains the dependent state but also engages the transition to dependence.

  • 13.
    Cippitelli, Andrea
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Karlsson, Camilla
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Shaw, Janice L.
    Eli Lilly, Indianapolis, IN, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Gehlert, Donald R.
    Eli Lilly, Indianapolis, IN, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Suppression of alcohol self-administration and reinstatement of alcohol seeking by melanin-concentrating hormone receptor 1 (MCH1-R) antagonism in Wistar rats2010In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 211, no 4, p. 367-375Article in journal (Refereed)
    Abstract [en]

    RATIONALE: Melanin-concentrating hormone (MCH) is involved in regulation of appetitive behaviors as well as emotional reactivity and reward, behavioral domains relevant to alcohol addiction.

    MATERIALS AND METHODS: We evaluated the effects of the non-peptide MCH1 receptor antagonist, GW803430 [6-(4-chloro-phenyl)-3-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3H-thieno[3,2-d]pyrimidin-4-one; 3-30 mg/kg, i.p.] on alcohol-related behaviors in Wistar rats.

    RESULTS: Ex vivo binding experiments demonstrated that the GW803430 dose range used resulted in high central MCH1 receptor occupancy. Alcohol self-administration was dose-dependently and potently suppressed, by approximately 80% at the highest dose. Reinstatement of alcohol-seeking induced by alcohol-associated cues was essentially eliminated. In contrast, reinstatement induced by footshock stress was not significantly altered. Taste preference for a quinine/saccharin solution, locomotor activity, and alcohol elimination were unaffected.

    CONCLUSION: Together, these observations support a specific involvement of the MCH system in mediating alcohol reward and cue-induced relapse to alcohol seeking. MCH1-R antagonism may constitute an attractive treatment target for alcohol use disorders.

  • 14.
    Cippitelli, Andrea
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Rezvani, Amir H.
    Duke University Medical Center, Durham, NC, USA.
    Robinson, J. Elliott
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Eisenberg, Lindsay
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Levin, Edward D.
    Duke University Medical Center, Durham, NC, USA.
    Bonaventure, Pascal
    Johnson & Johnson Pharmaceutical Research and Development, San Diego, USA.
    Motley, S. Timothy
    Johnson & Johnson Pharmaceutical Research and Development, San Diego, USA.
    Lovenberg, Timothy W.
    Johnson & Johnson Pharmaceutical Research and Development, San Diego, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    The novel, selective, brain-penetrant neuropeptide Y Y2 receptor antagonist, JNJ-31020028, tested in animal models of alcohol consumption, relapse, and anxiety2011In: Alcohol, ISSN 0741-8329, E-ISSN 1873-6823, Vol. 45, no 6, p. 567-576Article in journal (Refereed)
    Abstract [en]

    Neuropeptide Y (NPY) signaling has been shown to modulate stress responses and to be involved in regulation of alcohol intake and dependence. The present study explores the possibility that blockade of NPY Y2 autoreceptors using a novel, blood-brain barrier penetrant NPY Y2 receptor antagonist, JNJ-31020028 (N-(4-{4-[2-(diethylamino)-2-oxo-1-phenylethyl]piperazin-1-yl}-3-fluorophenyl)-2-pyridin-3-ylbenzamide), may achieve a therapeutically useful activation of the NPY system in alcohol- and anxiety-related behavioral models. We examined JNJ-31020028 in operant alcohol self-administration, stress-induced reinstatement to alcohol seeking, and acute alcohol withdrawal (hangover)-induced anxiety. Furthermore, we tested its effects on voluntary alcohol consumption in a genetic animal model of alcohol preference, the alcohol-preferring (P) rat. Neither systemic (0, 15, 30, and 40 mg/kg, subcutaneously [s.c.]) nor intracerebroventricular (0.0, 0.3, and 1.0 nmol/rat) administration of JNJ-31020028 affected alcohol-reinforced lever pressing or relapse to alcohol seeking behavior following stress exposure. Also, when its effects were tested on unlimited access to alcohol in P rats, preference for alcohol solution was transiently suppressed but without affecting voluntary alcohol intake. JNJ-31020028 (15 mg/kg, s.c.) did reverse the anxiogenic effects of withdrawal from a single bolus dose of alcohol on the elevated plus-maze, confirming the anxiolytic-like properties of NPY Y2 antagonism. Our data do not support Y2 antagonism as a mechanism for reducing alcohol consumption or relapse-like behavior, but the observed effects on withdrawal-induced anxiety suggest that NPY Y2 receptor antagonists may be a putative treatment for the negative affective states following alcohol withdrawal.

  • 15.
    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.

  • 16.
    Gehlert, Donald R.
    et al.
    Eli Lilly and Company, Indianapolis, IN, USA.
    Cippitelli, Andrea
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Lê, Anh Dzung
    University of Toronto, Canada.
    Hipskind, Philip A
    Eli Lilly and Company, Indianapolis, IN, USA.
    Hamdouchi, Chafiq
    Eli Lilly and Company, Indianapolis, IN, USA.
    Lu, Jianliang
    Eli Lilly and Company, Indianapolis, IN, USA.
    Hembre, Erik J.
    Eli Lilly and Company, Indianapolis, IN, USA.
    Cramer, Jeffrey
    Eli Lilly and Company, Indianapolis, IN, USA.
    Song, Min
    Eli Lilly and Company, Indianapolis, IN, USA.
    McKinzie, David
    Eli Lilly and Company, Indianapolis, IN, USA.
    Morin, Michelle
    Eli Lilly and Company, Indianapolis, IN, USA.
    Ciccocioppo, Roberto
    University of Camerino, Italy.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine: a novel brain-penetrant, orally available corticotropin-releasing factor receptor 1 antagonist with efficacy in animal models of alcoholism2007In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 27, no 10, p. 2718-2726Article in journal (Refereed)
    Abstract [en]

    We describe a novel corticotropin-releasing factor receptor 1 (CRF1) antagonist with advantageous properties for clinical development, and its in vivo activity in preclinical alcoholism models. 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (MTIP) inhibited 125I-sauvagine binding to rat pituitary membranes and cloned human CRF1 with subnanomolar affinities, with no detectable activity at the CRF2 receptor or other common drug targets. After oral administration to rats, MTIP inhibited 125I-sauvagine binding to rat cerebellar membranes ex vivo with an ED50 of approximately 1.3 mg/kg and an oral bioavailability of 91.1%. Compared with R121919 (2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylamino-pyrazolo[1,5-a]pyrimidine) and CP154526 (N-butyl-N-ethyl-4,9-dimethyl-7-(2,4,6-trimethylphenyl)-3,5,7-triazabicyclo[4.3.0]nona-2,4,8,10-tetraen-2-amine), MTIP had a markedly reduced volume of distribution and clearance. Neither open-field activity nor baseline exploration of an elevated plus-maze was affected by MTIP (1-10 mg/kg). In contrast, MTIP dose-dependently reversed anxiogenic effects of withdrawal from a 3 g/kg alcohol dose. Similarly, MTIP blocked excessive alcohol self-administration in Wistar rats with a history of dependence, and in a genetic model of high alcohol preference, the msP rat, at doses that had no effect in nondependent Wistar rats. Also, MTIP blocked reinstatement of stress-induced alcohol seeking both in postdependent and in genetically selected msP animals, again at doses that were ineffective in nondependent Wistar rats. Based on these findings, MTIP is a promising candidate for treatment of alcohol dependence.

  • 17.
    George, David T.
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Gilman, Jodi
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Hersh, Jacqueline
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Herion, David
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Geyer, Christopher
    National Institutes of Health, Bethesda, NIH; Bethesda, MD, USA.
    Peng, Xiaomei
    Lilly Research Laboratories, Indianapolis, IN, USA.
    Kielbasa, William
    Lilly Research Laboratories, Indianapolis, IN, USA.
    Rawlings, Robert
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Brandt, John E.
    Lilly Research Laboratories, Indianapolis, IN, USA.
    Gehlert, Donald R.
    Lilly Research Laboratories, Indianapolis, IN, USA.
    Tauscher, Johannes T.
    Lilly Research Laboratories, Indianapolis, IN, USA.
    Hunt, Stephen P.
    University College London, UK.
    Hommer, Daniel
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Neurokinin 1 receptor antagonism as a possible therapy for alcoholism2008In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 319, no 5869, p. 1536-1539Article in journal (Refereed)
    Abstract [en]

    Alcohol dependence is a major public health challenge in need of new treatments. As alcoholism evolves, stress systems in the brain play an increasing role in motivating continued alcohol use and relapse. We investigated the role of the neurokinin 1 receptor (NK1R), a mediator of behavioral stress responses, in alcohol dependence and treatment. In preclinical studies, mice genetically deficient in NK1R showed a marked decrease in voluntary alcohol consumption and had an increased sensitivity to the sedative effects of alcohol. In a randomized controlled experimental study, we treated recently detoxified alcoholic inpatients with an NK1R antagonist (LY686017; n = 25) or placebo (n = 25). LY686017 suppressed spontaneous alcohol cravings, improved overall well-being, blunted cravings induced by a challenge procedure, and attenuated concomitant cortisol responses. Brain functional magnetic resonance imaging responses to affective stimuli likewise suggested beneficial LY686017 effects. Thus, as assessed by these surrogate markers of efficacy, NK1R antagonism warrants further investigation as a treatment in alcoholism.

  • 18.
    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.

  • 19.
    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.

  • 20.
    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

  • 21.
    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

  • 22.
    Heilig, Markus
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Sommer, Wolfgang H.
    Central Institute of Mental Health, Mannheim, Germany.
    Hansson, Anita C.
    Central Institute of Mental Health, Mannheim, Germany.
    Ramchandani, Vijay A.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    George, David T.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Hommer, Daniel
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Barr, Christina S.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Translating the neuroscience of alcoholism into clinical treatments: from blocking the buzz to curing the blues2010In: Neuroscience and Biobehavioral Reviews, ISSN 0149-7634, E-ISSN 1873-7528, Vol. 35, no 2, p. 334-344Article in journal (Refereed)
    Abstract [en]

    Understanding the pathophysiology of addictive disorders is critical for development of new treatments. A major focus of addiction research has for a long time been on systems that mediate acute positively reinforcing effects of addictive drugs, most prominently the mesolimbic dopaminergic (DA) system and its connections. This research line has been successful in shedding light on the physiology of both natural and drug reward, but has not led to therapeutic breakthroughs. The role of classical reward systems is perhaps least clear in alcohol addiction. Here, recent work is summarized that points to some clinically important conclusions. First, important pharmacogenetic differences exist with regard to positively reinforcing effects of alcohol and the ability of this drug to activate classical reward pathways. This offers an opportunity for personalized treatment approaches in alcoholism. Second, brain stress and fear systems become pathologically activated in later stages of alcoholism and their activation is a major influence in escalation of alcohol intake, sensitization of stress responses, and susceptibility to relapse. These findings offer a new category of treatment mechanisms. Corticotropin-releasing hormone (CRH) signaling through CRH1 receptors is a major candidate target in this category, but recent data indicate that antagonists for substance P (SP) neurokinin 1 (NK1) receptors may have a similar potential.

  • 23.
    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.

  • 24.
    Karlsson, Camilla
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Schank, Jesse R.
    Department of Physiology and Pharmacology, University of Georgia, Athens, GA.
    Rehman, Faazal
    Laboratory of Clinical and Translational Studies, National Institute of Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD, USA.
    Stojakovic, Andrea
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Björk, Karl
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. 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.
    Solomon, Matthew
    Laboratory of Clinical and Translational Studies, National Institute of Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD, USA.
    Tapocik, Jenica
    Laboratory of Clinical and Translational Studies, National Institute of Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD, USA.
    Engblom, David
    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.
    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.
    Proinflammatory signaling regulates voluntary alcohol intake and stress-induced consumption after exposure to social defeat stress in mice2017In: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 22, no 5, p. 1279-1288Article in journal (Refereed)
    Abstract [en]

    Proinflammatory activity has been postulated to play a role in addictive processes and stress responses, but the underlying mechanisms remain largely unknown. Here, we examined the role of interleukin 1 (IL-1) and tumor necrosis factor-a (TNF-a) in regulation of voluntary alcohol consumption, alcohol reward and stress-induced drinking. Mice with a deletion of the IL-1 receptor I gene (IL-1RI KO) exhibited modestly decreased alcohol consumption. However, IL-1RI deletion affected neither the rewarding properties of alcohol, measured by conditioned place preference (CPP), nor stress-induced drinking induced by social defeat stress. TNF-a signaling can compensate for phenotypic consequences of IL1-RI deletion. We therefore hypothesized that double deletion of both IL-1RI and TNF-1 receptors (TNF-1R) may reveal the role of these pathways in regulation of alcohol intake. Double KOs consumed significantly less alcohol than control mice over a range of alcohol concentrations. The combined deletion of TNF-1R and IL-1RI did not influence alcohol reward, but did prevent increased alcohol consumption resulting from exposure to repeated bouts of social defeat stress. Taken together, these data indicate that IL-1RI and TNF-1R contribute to regulation of stress-induced, negatively reinforced drinking perhaps through overlapping signaling events downstream of these receptors, while leaving rewarding properties of alcohol largely unaffected.

  • 25.
    Karlsson, Camilla
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Zook, Michelle
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Ciccocioppo, Roberto
    University of Camerino, Italy.
    Gehlert, Donald R.
    Eli Lilly, Indianapolis, IN, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Cippitelli, Andrea
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Melanin-concentrating hormone receptor 1 (MCH1-R) antagonism: reduced appetite for calories and suppression of addictive-like behaviors2012In: Pharmacology, Biochemistry and Behavior, ISSN 0091-3057, E-ISSN 1873-5177, Vol. 102, no 3, p. 400-406Article in journal (Refereed)
    Abstract [en]

    RATIONALE: The hypothalamic neuropeptide melanin-concentrating hormone and its MCH1 receptor have been implicated in regulation of feeding and energy homeostasis, as well as modulation of reward-related behaviors. Here, we examined whether the MCH system plays a role both in caloric and motivational aspects of sugar intake.

    MATERIALS AND METHODS: The non-peptide MCH1-R antagonist GW803430 (3, 10, 30 mg/kg, i.p.) was first tested on self-administration under a fixed ratio schedule of reinforcement of both a caloric (10% w/v sucrose) and a non-caloric (0.06% w/v saccharin) sweet solution. GW803430 was then tested for its ability to alter motivational properties and seeking of sucrose. Lastly, the drug was tested to concurrently examine its effects on the escalated consumption of both sugar and food in animals following intermittent sugar access.

    RESULTS: The MCH1-R antagonist reduced sucrose- but not saccharin-reinforced lever pressing, likely reflecting a decreased appetite for calories in GW803430-treated rats. GW803430 reduced sucrose self-administration under a progressive ratio schedule, and suppressed cue-induced reinstatement of sucrose seeking, suggesting effects on rewarding properties of sucrose. GW803430 attenuated food intake in rats on intermittent access to sucrose at all doses examined (3, 10, 30 mg/kg), while reduction of sugar intake was weaker in magnitude.

    CONCLUSION: Together, these observations support an involvement of the MCH system in regulation of energy balance as well as mediation of sucrose reward. MCH may be an important regulator of sugar intake by acting on both caloric and rewarding components.

  • 26.
    Karlsson, Rose-Marie
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Choe, Jessica S.
    National Institute of Mental Health, NIH, Bethesda, MD, USA .
    Cameron, Heather A
    National Institute of Mental Health, NIH, Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Crawley, Jacqueline N
    National Institute of Mental Health, NIH, Bethesda, MD, USA.
    Holmes, Andrew
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    The neuropeptide Y Y1 receptor subtype is necessary for the anxiolytic-like effects of neuropeptide Y, but not the antidepressant-like effects of fluoxetine, in mice2008In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 195, no 4, p. 547-557Article in journal (Refereed)
    Abstract [en]

    RATIONALE: Neuropeptide Y (NPY) is implicated in the pathophysiology of affective illness. Multiple receptor subtypes (Y1R, Y2R, and Y5R) have been suggested to contribute to NPY's effects on rodent anxiety and depression-related behaviors.

    OBJECTIVES: To further elucidate the role of Y1R in (1) NPY's anxiolytic-like effects and (2) fluoxetine's antidepressant-like and neurogenesis-inducing effects.

    METHODS: Mice lacking Y1R were assessed for spontaneous anxiety-like behavior (open field, elevated plus-maze, and light/dark exploration test) and Pavlovian fear conditioning, and for the anxiolytic-like effects of intracerebroventricularly (icv)-administrated NPY (elevated plus-maze). Next, Y1R -/- were assessed for the antidepressant-like effects of acute fluoxetine in the forced swim test and chronic fluoxetine in the novelty-induced hypophagia test, as well as for chronic fluoxetine-induced hippocampal neurogenesis.

    RESULTS: Y1R -/- exhibited largely normal baseline behavior as compared to +/+ littermate controls. Intraventricular administration of NPY in Y1R -/- mice failed to produce the normal anxiolytic-like effect in the elevated plus-maze test seen in +/+ mice. Y1R mutant mice showed higher immobility in the forced swim test and longer latencies in the novelty-induced hypophagia test. In addition, Y1R -/- mice responded normally to the acute and chronic effects of fluoxetine treatment in the forced swim test and the novelty-induced hypophagia test, respectively, as well as increased neuronal precursor cell proliferation in the hippocampus.

    CONCLUSIONS: These data demonstrate that Y1R is necessary for the anxiolytic-like effects of icv NPY, but not for the antidepressant-like or neurogenesis-inducing effects of fluoxetine. The present study supports targeting Y1R as a novel therapeutic target for anxiety disorders.

  • 27.
    Lindell, S. G.
    et al.
    Laboratory of Comparative Behavioral Genomics, NIH/NIAAA/LNG, USA; Laboratory of Clinical and Translational Studies, National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism, NIH Animal Center, USA.
    Schwandt, M. L.
    Laboratory of Clinical and Translational Studies, National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism, NIH Animal Center, USA.
    Suomi, S. J.
    Laboratory of Comparative Ethology, National Institutes of Health/National Institute of Child Health and Human Development, NIH Animal Center, USA.
    Rice, K. C.
    Chemical Biology Research Branch, National Institute on Drug Abuse, Bethesda, 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. Laboratory of Clinical and Translational Studies, National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism, NIH Animal Center, USA.
    Barr, C. S.
    Laboratory of Comparative Behavioral Genomics, NIH/NIAAA/LNG, USA; Laboratory of Clinical and Translational Studies, National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism, NIH Animal Center, USA.
    Intermittent Access to Ethanol Induces Escalated Alcohol Consumption in Primates2017In: Journal of addictive behaviors, therapy and rehabilitation, ISSN 2324-9005, Vol. 6, no 1Article in journal (Refereed)
    Abstract [en]

    Escalation of voluntary alcohol drinking is characteristic of alcohol addiction and can be induced in rodents using intermittent access to alcohol. This model has been used to evaluate candidate therapeutics, but key systems involved in the transition into alcohol addiction, such as CRF, differ in their organization between rodents and primates. We examined the ability of an intermittent access schedule to induce escalation of voluntary alcohol drinking in non-human primates and used this model to assess the role of corticotropin releasing hormone (CRF) signaling in this process.

  • 28.
    Mahmoud, Saifeldin
    et al.
    Penn State College of Medicine, Hershey, PA, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Sommer, Wolfgang H.
    University of Heidelberg, Germany.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Holgate, Joan K.
    Ernest Gallo Clinic and Research Center, University of California-San Francisco, Emeryville, CA, USA.
    Bartlett, Selena E.
    Ernest Gallo Clinic and Research Center, University of California-San Francisco, Emeryville, CA, USA.
    Ruiz-Velasco, Victor
    Penn State College of Medicine, Hershey, PA, USA.
    Pharmacological consequence of the A118G μ opioid receptor polymorphism on morphine- and fentanyl-mediated modulation of Ca²⁺ channels in humanized mouse sensory neurons2011In: Anesthesiology, ISSN 0003-3022, E-ISSN 1528-1175, Vol. 115, no 5, p. 1054-1062Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The most common functional single nucleotide polymorphism of the human OPRM1 gene, A118G, has been shown to be associated with interindividual differences in opioid analgesic requirements, particularly with morphine, in patients with acute postoperative pain. The purpose of this study was to examine whether this polymorphism would modulate the morphine and fentanyl pharmacological profile of sensory neurons isolated from a humanized mouse model homozygous for either the 118A or 118G allele.

    METHODS: The coupling of wild-type and mutant μ opioid receptors to voltage-gated Ca channels after exposure to either ligand was examined by employing the whole cell variant of the patch-clamp technique in acutely dissociated trigeminal ganglion neurons. Morphine-mediated antinociception was measured in mice carrying either the 118AA or 118GG allele.

    RESULTS: The biophysical parameters (cell size, current density, and peak current amplitude potential) measured from both groups of sensory neurons were not significantly different. In 118GG neurons, morphine was approximately fivefold less potent and 26% less efficacious than that observed in 118AA neurons. On the other hand, the potency and efficacy of fentanyl were similar for both groups of neurons. Morphine-mediated analgesia in 118GG mice was significantly reduced compared with the 118AA mice.

    CONCLUSIONS: This study provides evidence to suggest that the diminished clinical effect observed with morphine in 118G carriers results from an alteration of the receptor's pharmacology in sensory neurons. In addition, the impaired analgesic response with morphine may explain why carriers of this receptor variant have an increased susceptibility to become addicted to opioids.

  • 29.
    Mayo, Leah M
    et al.
    University of Chicago, IL 60637 USA .
    Fraser, Diana
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. NIAAA, MD 20892 USA .
    Childs, Emma
    University of Chicago, IL 60637 USA .
    Momenan, Reza
    NIAAA, MD 20892 USA .
    Hommer, Daniel W
    NIAAA, MD 20892 USA .
    de Wit, Harriet
    University of Chicago, IL 60637 USA .
    Heilig, Markus
    NIAAA, MD 20892 USA .
    Conditioned Preference to a Methamphetamine-Associated Contextual Cue in Humans2013In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 38, no 6, p. 921-929Article in journal (Refereed)
    Abstract [en]

    Classical conditioning is widely used to study motivational properties of addictive drugs in animals, but has rarely been used in humans. We established a procedure suitable for studying the neurobiology and individual determinants of classical conditioning in humans. Healthy volunteers were randomly assigned to four groups that received methamphetamine or placebo in the presence of distinctive environmental cues under paired or unpaired conditions. During each session, subjects performed tasks known to activate the ventral striatum. Tasks were performed in the presence of a distinctive context, consisting of a screen background image of a beach or mountains, accompanied by corresponding sounds. Separate groups of subjects carried out the tasks under high ($35-50) or low ($5-20) reward conditions. Within each of the two reward conditions, one group (paired) received methamphetamine (20 mg, oral) or placebo consistently associated with one of the contexts, while the other (unpaired) received drug or placebo unrelated to context. A fifth group (paired) performed the tasks with contextual cues but in the absence of monetary incentives. Before and after conditioning, participants carried out a series of forced choice tasks for the contextual cues, and change of preference over time was analyzed. All paired groups showed a significant increase in preference for the drug-associated context, with a linear trend for increase across the levels of reward. Preference was unrelated to subjective drug effects, and did not change in the unpaired group. These data support the translational utility of our conditioning procedure for studies of reward mechanisms in humans.

  • 30.
    Patnaik, S.
    et al.
    NIH, Bethesda, MD, USA.
    Marugan, J.
    NIH, Bethesda, MD, USA.
    Liu, K.
    NIH, Bethesda, MD, USA.
    Zheng, W.
    NIH, Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Eskay, R.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Southall, N.
    NIH, Bethesda, MD, USA.
    Heilig, Marcus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Inglese, J.
    NIH, Bethesda, MD, USA.
    Austin, C.
    NIH, Bethesda, MD, USA.
    Identification of small molecule antagonists of the neuropeptide S receptor2010In: Probe Reports from the NIH Molecular Libraries Program [Internet], National Center for Biotechnology Information (US) , 2010Chapter in book (Other academic)
  • 31.
    Patnaik, Samarjit
    et al.
    NIH, Bethesda, MD, USA.
    Marugan, Juan J.
    NIH, Bethesda, MD, USA.
    Liu, Ke
    NIH, Bethesda, MD, USA.
    Zheng, Wei
    NIH, Bethesda, MD, USA.
    Southall, Noel
    NIH, Bethesda, MD, USA.
    Dehdashti, Seameen J.
    NIH, Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Bell, Lauren
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Zook, Michelle
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Eskay, Bob
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Brimacombe, Kyle R.
    NIH, Bethesda, MD, USA.
    Austin, Christopher P.
    NIH, Bethesda, MD, USA.
    Structure-Activity Relationship of Imidazopyridinium Analogues as Antagonists of Neuropeptide S Receptor2013In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 56, no 22, p. 9045-9056Article in journal (Refereed)
    Abstract [en]

    The discovery and characterization of a novel chemical series of phosphorothioyl-containing imidazopyridines as potent neuropeptide S receptor antagonists is presented. The synthesis of analogues and their structure-activity relationship with respect to the Gq, Gs, and ERK pathways is detailed. The pharmacokinetics and in vivo efficacy of a potent analogue in a food intake rodent model are also included, underscoring its potential therapeutic value for the treatment of sleep, anxiety, and addiction disorders.

  • 32.
    Ramchandani, V A
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Umhau, J
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Pavon, F J
    The Scripps Research Institute, La Jolla, CA, USA.
    Ruiz-Velasco, V
    PennState College of Medicin, Hershey, PA, USA.
    Margas, W
    PennState College of Medicin, Hershey, PA, USA.
    Sun, H
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Damadzic, R
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Eskay, R
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Schoor, M
    TaconicArtemis GmbH, Köln, Germany.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Schwandt, M L
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Sommer, W H
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    George, D T
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Parsons, L H
    The Scripps Research Institute, La Jolla, CA, USA.
    Herscovitch, P
    National Institutes of Health, Bethesda, MD, USA.
    Hommer, D
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Heilig, Marcus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    A genetic determinant of the striatal dopamine response to alcohol in men2011In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 16, no 8, p. 809-817Article in journal (Refereed)
    Abstract [en]

    Excessive alcohol use, a major cause of morbidity and mortality, is less well understood than other addictive disorders. Dopamine release in ventral striatum is a common element of drug reward, but alcohol has an unusually complex pharmacology, and humans vary greatly in their alcohol responses. This variation is related to genetic susceptibility for alcoholism, which contributes more than half of alcoholism risk. Here, we report that a functional OPRM1 A118G polymorphism is a major determinant of striatal dopamine responses to alcohol. Social drinkers recruited based on OPRM1 genotype were challenged in separate sessions with alcohol and placebo under pharmacokinetically controlled conditions, and examined for striatal dopamine release using positron emission tomography and [(11)C]-raclopride displacement. A striatal dopamine response to alcohol was restricted to carriers of the minor 118G allele. To directly establish the causal role of OPRM1 A118G variation, we generated two humanized mouse lines, carrying the respective human sequence variant. Brain microdialysis showed a fourfold greater peak dopamine response to an alcohol challenge in h/mOPRM1-118GG than in h/mOPRM1-118AA mice. OPRM1 A118G variation is a genetic determinant of dopamine responses to alcohol, a mechanism by which it likely modulates alcohol reward.

  • 33.
    Rimondini, Roberto
    et al.
    Karolinska Institutet, Huddinge University Hospital, Sweden.
    Thorsell, Annika
    National Institutes of Health, NIAAA, Bethesda, MD, USA.
    Heilig, Markus
    National Institutes of Health, NIAAA, Bethesda, MD, USA.
    Suppression of ethanol self-administration by the neuropeptide Y (NPY) Y2 receptor antagonist BIIE0246: evidence for sensitization in rats with a history of dependence2005In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 375, no 2, p. 129-133Article in journal (Refereed)
    Abstract [en]

    Evidence from genetically modified mice suggests a role for NPY in regulation of ethanol intake, but results of pharmacological studies have been more variable. We have previously shown that potentiation of NPY signaling through antagonism at NPY-Y2 receptors decreases operant responding for ethanol in Wistar rats without a history of dependence. Here, we examined the effects of Y2-antagonism in animals with a history of dependence induced by long-term intermittent exposure to ethanol vapor. The Y2-receptor antagonist BIIE0246 suppressed operant responding for ethanol (approximately 50%, p=0.01), at a dose (0.5 nmol i.c.v.) which was ineffective in subjects without a history of dependence. Responding for the ethanol-free control solution was unaffected. These data confirm that antagonism at central NPY-Y2 receptors selectively suppresses motivation to self-administer ethanol, and indicate that the NPY system is sensitized in animals with a history of dependence. This may render the NPY system, and Y2 receptors in particular, an attractive target for treatment of alcohol dependence.

  • 34.
    Rinker, Jennifer A.
    et al.
    American University, Washington, DC, USA.
    Hutchison, Mary Anne
    American University, Washington, DC, USA.
    Chen, Scott A.
    National Institute on Drug Abuse, NIH, Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Riley, Anthony L.
    American University, Washington, DC, USA.
    Exposure to nicotine during periadolescence or early adulthood alters aversive and physiological effects induced by ethanol2011In: Pharmacology, Biochemistry and Behavior, ISSN 0091-3057, E-ISSN 1873-5177, Vol. 99, no 1, p. 7-16Article in journal (Refereed)
    Abstract [en]

    The majority of smokers begin their habit during adolescence, which often precedes experimentation with alcohol. Interestingly, very little preclinical work has been done examining how exposure to nicotine during periadolescence impacts the affective properties of alcohol in adulthood. Understanding how periadolescent nicotine exposure influences the aversive effects of alcohol might help to explain why it becomes more acceptable to this preexposed population. Thus, Experiment 1 exposed male Sprague Dawley rats to either saline or nicotine (0.4mg/kg, IP) from postnatal days 34 to 43 (periadolescence) and then examined changes in the aversive effects of alcohol (0, 0.56, 1.0 and 1.8g/kg, IP) in adulthood using the conditioned taste aversion (CTA) design. Changes in blood alcohol concentration (BAC) as well as alcohol-induced hypothermia and locomotor suppression were also assessed. To determine if changes seen were specific to nicotine exposure during periadolescence, the procedures were replicated in adults (Experiment 2). Preexposure to nicotine during periadolescence attenuated the acquisition of the alcohol-induced CTAs (at 1.0g/kg) and the hypothermic effects of alcohol (1.0g/kg). Adult nicotine preexposure produced similar attenuation in alcohol's aversive (at 1.8g/kg) and hypothermic (1.8g/kg) effects. Neither adolescent nor adult nicotine preexposure altered BACs or alcohol-induced locomotor suppression. These results suggest that nicotine may alter the aversive and physiological effects of alcohol, regardless of the age at which exposure occurs, possibly increasing its overall reinforcing value and making it more likely to be consumed.

  • 35.
    Robinson, J. E.
    et al.
    University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
    Fish, E. W.
    University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
    Krouse, M. C.
    University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Heilig, Marcus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Malanga, C. J.
    University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
    Potentiation of brain stimulation reward by morphine: effects of neurokinin-1 receptor antagonism2012In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 220, no 1, p. 215-224Article in journal (Refereed)
    Abstract [en]

    RATIONALE: The abuse potential of opioids may be due to their reinforcing and rewarding effects, which may be attenuated by neurokinin-1 receptor (NK1R) antagonists.

    OBJECTIVE: This study was conducted to measure the effects of opioid and NK1R blockade on the potentiation of brain stimulation reward (BSR) by morphine using the intracranial self-stimulation method.

    METHODS: Adult male C57BL/6J mice (n = 15) were implanted with unipolar stimulating electrodes in the lateral hypothalamus and trained to respond for varying frequencies of rewarding electrical stimulation. The BSR threshold (θ(0)) and maximum response rate (MAX) were determined before and after intraperitoneal administration of saline, morphine (1.0-17.0 mg/kg), or the NK1R antagonists L-733,060 (1.0-17.0 mg/kg) and L-703,606 (1.0-17.0 mg/kg). In morphine antagonism experiments, naltrexone (0.1-1.0 mg/kg) or 10.0 mg/kg L-733,060 or L-703,606 was administered 15 min before morphine (1.0-10.0 mg/kg) or saline.

    RESULTS: Morphine dose-dependently decreased θ(0) (maximum effect = 62% of baseline) and altered MAX when compared to saline. L-703,606 and L-733,060 altered θ(0); 10.0 mg/kg L-733,060 and L-703,606, which did not affect θ(0) or MAX, attenuated the effects of 3.0 and 10.0 mg/kg morphine, and 1.0 and 0.3 mg/kg naltrexone blocked the effects of 10.0 mg/kg morphine. Naltrexone given before saline did not affect θ(0) or MAX.

    CONCLUSIONS: The decrease in θ(0) by morphine reflects its rewarding effects, which were attenuated by NK1R and opioid receptor blockade. These results demonstrate the importance of substance P signaling during limbic reward system activation by opioids.

  • 36.
    Schank, Jesse R.
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Goldstein, Andrea L.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Rowe, Kelly E.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    King, Courtney E.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Marusich, Julie A.
    Research Triangle Institute, Research Triangle Park, NC, USA.
    Wiley, Jenny L.
    Research Triangle Institute, Research Triangle Park, NC, USA.
    Carroll, F. Ivy
    Research Triangle Institute, Research Triangle Park, NC, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    The kappa opioid receptor antagonist JDTic attenuates alcohol seeking and withdrawal anxiety2012In: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 17, no 3, p. 634-647Article in journal (Refereed)
    Abstract [en]

    The role of kappa-opioid receptors (KOR) in the regulation of alcohol-related behaviors is not completely understood. For example, alcohol consumption has been reported to increase following treatment with KOR antagonists in rats, but was decreased in mice with genetic deletion of KOR. Recent studies have further suggested that KOR antagonists may selectively decrease alcohol self-administration in rats following a history of dependence. We assessed the effects of the KOR antagonist JDTic on alcohol self-administration, reinstatement of alcohol seeking induced by alcohol-associated cues or stress, and acute alcohol withdrawal-induced anxiety ('hangover anxiety'). JDTic dose-dependently reversed hangover anxiety when given 48 hours prior to testing, a time interval corresponding to the previously demonstrated anxiolytic efficacy of this drug. In contrast, JDTic decreased alcohol self-administration and cue-induced reinstatement of alcohol seeking when administered 2 hours prior to testing, but not at longer pre-treatment times. For comparison, we determined that the prototypical KOR antagonist nor-binaltorphimine can suppress self-administration of alcohol at 2 hours pre-treatment time, mimicking our observations with JDTic. The effects of JDTic were behaviorally specific, as it had no effect on stress-induced reinstatement of alcohol seeking, self-administration of sucrose, or locomotor activity. Further, we demonstrate that at a 2 hours pre-treatment time JDTic antagonized the antinociceptive effects of the KOR agonist U50,488H but had no effect on morphine-induced behaviors. Our results provide additional evidence for the involvement of KOR in regulation of alcohol-related behaviors and provide support for KOR antagonists, including JDTic, to be evaluated as medications for alcoholism.

  • 37.
    Schank, Jesse R.
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Pickens, Charles L.
    National Institute on Drug Abuse, NIH, Bethesda, MD, USA.
    Rowe, Kelly E.
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Cheng, Kejun
    National Institute on Drug Abuse, NIH, Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Rice, Kenner C.
    National Institute on Drug Abuse, NIH, Bethesda, MD, USA.
    Shaham, Yavin
    National Institute on Drug Abuse, NIH, Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Stress-induced reinstatement of alcohol-seeking in rats is selectively suppressed by the neurokinin 1 (NK1) antagonist L8224292011In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 218, no 1, p. 111-119Article in journal (Refereed)
    Abstract [en]

    RATIONALE: Genetic inactivation or pharmacological antagonism of neurokinin 1 (NK1) receptors blocks morphine and alcohol reward in rodents, while NK1 antagonism decreases alcohol craving in humans. The role of the NK1 system for relapse-like behavior has not previously been examined.

    OBJECTIVE: Divergence between human and rodent NK1 receptors has limited the utility of NK1 antagonists developed for the human receptor species for preclinical studies of addiction-related behaviors in rats. Here we used L822429, an NK1 antagonist specifically engineered to bind at high affinity to the rat receptor, to assess the effects of NK1 receptor antagonism on alcohol-seeking behaviors in rats.

    METHODS: L822429 (15 and 30 mg/kg) was used to examine effects of NK1 receptor antagonism on operant self-administration of 10% alcohol in 30-min daily sessions, as well as intermittent footshock stress- and cue-induced reinstatement of alcohol-seeking after extinction of lever responding.

    RESULTS: At the doses used, L822429 did not significantly affect alcohol self-administration or cue-induced reinstatement, but potently and dose dependently suppressed stress-induced reinstatement of alcohol seeking, with an essentially complete suppression at the highest dose. The effect of L822429 on stress-induced reinstatement was behaviorally specific. The drug had no effect on conditioned suppression of operant responding following fear conditioning, locomotor activity, or self-administration of a sucrose solution.

    CONCLUSIONS: To the degree that the reinstatement model provides a model of drug relapse, the results provide support for NK1 antagonism as a promising mechanism for pharmacotherapy of alcoholism, acting through suppression of stress-induced craving and relapse.

  • 38.
    Sells, Joanna R.
    et al.
    NIAAA, MD 20892 USA; Uniformed Serv University of Health Science, MD 20814 USA.
    Waters, Andrew J.
    Uniformed Serv University of Health Science, MD 20814 USA.
    Schwandt, Melanie L.
    NIAAA, MD 20814 USA.
    Kwako, Laura E.
    NIAAA, MD 20814 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.
    George, David T.
    NIAAA, MD 20814 USA.
    Ramchandani, Vijay A.
    NIAAA, MD 20892 USA.
    Characterization of comorbid PTSD in treatment-seeking alcohol dependent inpatients: Severity and personality trait differences2016In: Drug And Alcohol Dependence, ISSN 0376-8716, E-ISSN 1879-0046, Vol. 163, p. 242-246Article in journal (Refereed)
    Abstract [en]

    Background: Post-traumatic stress disorder (PTSD) is often comorbid with alcohol dependence (AD), but little is known about the characteristics of AD treatment-seeking inpatients with PTSD. We examined differences between treatment-seeking alcohol dependent inpatients with and without comorbid PTSD. We hypothesized that those with AD and PTSD would have higher levels of: (1) alcohol use and AD severity; (2) anxiety and mood disorders; (3) neuroticism. Methods: Individuals (N = 411, mean age = 41.7 +/- 10.0 years) with AD were monitored over 30 days in a suburban inpatient alcohol treatment setting. Patients were evaluated to identify AD and comorbid PTSD, mood and anxiety disorders, alcohol use and dependence severity, personality, and aggression. Results: Those with PTSD (19% of the sample) did not differ in the amount of alcohol consumed, but had greater: (1) severity of AD (p = 0.001, d = 0.44); (2) diagnosis of anxiety (p = 0.000, OR = 3.64) and mood (p = 0.000, OR = 4.83) disorders; and (3) levels of neuroticism (p amp;lt; 0.001, d = 0.67) and aggression (p amp;lt; 0.001, d = 0.81). Conclusions: AD patients with comorbid PTSD present a more severe phenotype across AD severity, frequency of anxiety and mood disorders, and levels of neuroticism and aggression. This group may benefit from concurrent treatment of both AD and PTSD. Future research can investigate neuroticism as a potential treatment target. Published by Elsevier Ireland Ltd.

  • 39.
    Skinbjerg, Mette
    et al.
    National Institutes of Health, NIH, Bethesda, MD, USA.
    Ariano, Marjorie A.
    The Chicago Medical School at Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Halldin, Christer
    Karolinska Institutet, Stockholm, Sweden.
    Innis, Robert B.
    National Institute of Mental Health, NIH, Bethesda, MD, USA.
    Sibley, David R.
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Arrestin3 mediates D(2) dopamine receptor internalization2009In: Synapse, ISSN 0887-4476, E-ISSN 1098-2396, Vol. 63, no 7, p. 621-624Article in journal (Refereed)
  • 40.
    Skinbjerg, Mette
    et al.
    National Institute of Mental Health, Bethesda, MD, USA.
    Liow, Jeih-San
    National Institute of Mental Health, Bethesda, MD, USA.
    Seneca, Nicholas
    National Institute of Mental Health, Bethesda, MD, USA.
    Hong, Jinsoo
    National Institute of Mental Health, Bethesda, MD, USA.
    Lu, Shuiyu
    National Institute of Mental Health, Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Pike, Victor W.
    National Institute of Mental Health, Bethesda, MD, USA.
    Halldin, Christer
    Karolinska Institutet, Stockholm, Sweden.
    Sibley, David R.
    National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
    Innis, Robert B.
    National Institute of Mental Health, Bethesda, MD, USA.
    D2 dopamine receptor internalization prolongs the decrease of radioligand binding after amphetamine: a PET study in a receptor internalization-deficient mouse model2010In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 50, no 4, p. 1402-1407Article in journal (Refereed)
    Abstract [en]

    Dopamine released by amphetamine decreases the in vivo binding of PET radioligands to the dopamine D(2) receptor. Although concentrations of extracellular dopamine largely return to baseline within 1 to 2 h after amphetamine treatment, radioligand binding remains decreased for several hours. The purpose of this study was to determine whether the prolonged decrease of radioligand binding after amphetamine administration is caused by receptor internalization. To distinguish dopamine displacement from receptor internalization, we used wild-type and arrestin3 (arr3) knockout mice, which are incapable of internalizing D(2) receptors. In addition, we used both the D(2) selective agonist [(11)C]MNPA (which is thought to bind to the high affinity state of the receptor) and the D(2) selective antagonist [(18)F]fallypride (which does not differentiate between high and low affinity state). After an initial baseline scan, animals were divided in three groups for a second scan: either 30 min or 4 h after amphetamine administration (3 mg/kg, i.p.) or as retest. At 30 min, [(11)C]MNPA showed greater displacement than [(18)F]fallypride, but each radioligand gave similar displacement in knockout and wild-type mice. At 4 h, the binding of both radioligands returned to baseline in arr3 knockout mice, but remained decreased in wild-type mice. Radioligand binding was unaltered on retest scanning. Our results suggest that the prolonged decrease of radioligand binding after amphetamine is mainly due to internalization of the D(2) receptor rather than dopamine displacement. In addition, this study demonstrates the utility of small animal PET to study receptor trafficking in vivo in genetically modified mice.

  • 41.
    Thorsell, Annika
    et al.
    Magnus Huss Clinic, Karolinska Hospital, S-17176 Stockholm, Sweden.
    Blomqvist, Anders G
    Department of Medical Genetics, Uppsala University, Uppsala, Sweden.
    Heilig, Markus
    Magnus Huss Clinic, Karolinska Hospital, S-17176 Stockholm, Sweden.
    Cationic lipid-mediated delivery and expression of prepro-neuropeptide Y cDNA after intraventricular administration in rat: feasibility and limitations.1996In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 61, no 3, p. 205-211Article in journal (Refereed)
    Abstract [en]

    The utility of in vivo lipofection for delivery and expression of a neuropeptide gene in the adult rat brain was explored. Prepro-neuropeptide Y (NPY) cDNA was cloned into the episomal eucaryotic expression vector pCEP4. This construct was complexed to lipofectamine or lipofectin. Complexed DNA was injected into the lateral ventricles of adult rats. Brains were removed for analysis following various time intervals. Polymerase chain reaction (PCR) reactions were designed for specific detection of endogenous and vector derived NPY sequence, respectively. PCR of DNA preparations from 5 major brain regions (frontal and parietal cortex, striatum, hypothalamus, brain stem) demonstrated presence of vector DNA up to 1 month (longest interval studied) in all brain regions. Reverse-transcription (RT-) PCR of DNase treated RNA-preparations from brain tissue demonstrated presence of both vector-derived and endogenous NPY mRNA in treated animals, while only endogenous mRNA was detected in controls. In situ hybridization histochemistry indicated scattered patches of vector uptake into tissue in the vicinity of the CSF compartment, but not into deeper located structures. Weight gain was not affected, indicating that the expression levels achieved may not be sufficient to play a functional role, and/or may need to be targeted to specific brain areas. These findings suggest a potential for cationic lipid mediated gene transfer in the brain as an experimental tool and as a possible future therapeutic principle, but also indicate the need for optimization of delivery strategies in order to achieve functionally relevant expression levels.

  • 42.
    Thorsell, Annika
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Johnson, Justin
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Effect of the adenosine A2a receptor antagonist 3,7-dimethyl-propargylxanthine on anxiety-like and depression-like behavior and alcohol consumption in Wistar Rats2007In: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 31, no 8, p. 1302-1307Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: It has been suggested that the reinforcing properties of ethanol are in part mediated via an A2 activation of cAMP/PKA signaling in the nucleus accumbens, predicting that administration of an A2a antagonist might reduce ethanol reward and consumption. We therefore examined the effect of the adenosine A2a receptor antagonist 3,7-dimethylpropargylxanthine (DMPX, 3, and 10 mg/kg intraperitoneal) on alcohol reinforcement, anxiety-related, depression, and rewarding behaviors in nonselected Wistar rats.

    METHODS: Operant ethanol self-administration was used for examining alcohol intake, elevated plus-maze and Vogel conflict test for anxiety-related behavior, Porsolt swim test for depression-like behavior, and conditioned place preference for examination of the rewarding properties of the drug.

    RESULTS: 3,7-Dimethylpropargylxanthine decreased lever-pressing for ethanol in a dose-dependent manner. When analyzed as percentage of pretreatment baseline, maximum suppression was approximately 60% (39+/-7.5 vs 98+/-12%, mean+/-SEM, p=0.017). This effect was behaviorally specific, as no effect was found on the water lever. In agreement with previously published data, stimulation of locomotion was found (beam-breaks: 3590+/-540 vs 2475+/-240, 10 mg/kg vs saline, p=0.048). No anxiety-modulating effects were seen in either the elevated plus-maze or the Vogel conflict test. 3,7-Dimethylpropargylxanthine was not found to have intrinsic rewarding properties in the conditioned place preference model.

    CONCLUSIONS: In summary, DMPX produced a robust and behaviorally selective reduction of ethanol reinforcement, while anxiety-modulating effects were less consistent. These results bring further support to a role for adenosine in the regulation of ethanol consumption and possibly alcohol addiction/abuse, and the A2a receptor as a potential target for the treatment of alcoholism and alcohol abuse.

  • 43.
    Thorsell, Annika
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Karlsson, Rose-Marie
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    NPY in alcoholism and psychiatric disorders2006In: NPY Family of Peptides in Neurobiology, Cardiovascular and Metabolic Disorders: from Genes to Therapeutics / [ed] Zofia Zukowska, Giora Z. Feuerstein, Basel: Birkhäuser Verlag, 2006, Vol. 95, p. 183-192Chapter in book (Refereed)
    Abstract [en]

    The NPY system may well be one of the most interesting target systems for development of treatments for alcohol dependence as well as mood disorders such as depression and anxiety syndromes. NPY is an endogenous anxiolytic compound, functions as an antidepressant, and is effective in modifying alcohol intake in high drinking states. Through receptor subtype specific compounds, the NPY system offers an interesting and innovative future approach for treatment designs. Selective Y2 receptor antagonists and/or Y1 agonists that are peripherally available and effectively penetrate the CNS are possible candidates. In conclusion, the NPY system offers attractive targets for development of future treatments for depression, anxiety, and alcohol dependence.

  • 44.
    Thorsell, Annika
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Schank, Jesse R.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Singley, Erick
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Hunt, Stephen P
    University College London, UK.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Neurokinin-1 receptors (NK1Rs), alcohol consumption, and alcohol reward in mice2010In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 209, no 1, p. 103-111Article in journal (Refereed)
    Abstract [en]

    RATIONALE: Reduced voluntary alcohol consumption was recently found in neurokinin-1 receptor (NK1R)-deficient (KO) mice. It remains unknown whether this reflects developmental effects or direct regulation of alcohol consumption by NK1R:s, and whether the reduced consumption reflects motivational effects.

    OBJECTIVE: The objective of this study is to obtain an expanded preclinical validation of NK1R antagonism as a candidate therapeutic mechanism in alcohol use disorders.

    METHODS: The NK1R antagonist L-703,606 and NK1R KO mice were used in models that assess alcohol-related behaviors.

    RESULTS: L-703,606 (3-10 mg/kg i.p.) dose-dependently suppressed alcohol intake in WT C57BL/6 mice under two-bottle free choice conditions but was ineffective in NK1R KO:s, demonstrating the receptor specificity of the effect. Alcohol reward, measured as conditioned place preference for alcohol, was reduced by NK1R receptor deletion in a gene dose-dependent manner. In a model where escalation of intake is induced by repeated cycles of deprivation and access, escalation was seen in WT mice, but not in KO mice. Among behavioral phenotypes previously reported for NK1R mice on a mixed background, an analgesic-like phenotype was maintained on the C57BL/6 background used here, while KO:s and WT:s did not differ in anxiety- and depression-related behaviors.

    CONCLUSIONS: Acute blockade of NK1R:s mimics the effects of NKR1 gene deletion on alcohol consumption, supporting a direct rather than developmental role of the receptor in regulation of alcohol intake. Inactivation of NK1R:s critically modulates alcohol reward and escalation, two key characteristics of addiction. These data provide critical support for NK1R antagonism as a candidate mechanism for treatment of alcoholism.

  • 45.
    Thorsell, Annika
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Tapocik, Jenica D
    Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
    Liu, Ke
    National Center for Advancing Translational Sciences, Bethesda, Maryland, USA.
    Zook, Michelle
    Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
    Bell, Lauren
    Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
    Flanigan, Meghan
    Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
    Patnaik, Samarjit
    National Center for Advancing Translational Sciences, Bethesda, Maryland, USA.
    Marugan, Juan
    National Center for Advancing Translational Sciences, Bethesda, Maryland, USA.
    Damadzic, Ruslan
    Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
    Dehdashti, Seameen J
    National Center for Advancing Translational Sciences, Bethesda, Maryland, USA.
    Schwandt, Melanie L
    Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
    Southall, Noel
    National Center for Advancing Translational Sciences, Bethesda, Maryland, USA.
    Austin, Christopher P
    National Center for Advancing Translational Sciences, Bethesda, Maryland, USA.
    Eskay, Robert
    Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
    Ciccocioppo, Roberto
    University of Camerino, Italy.
    Zheng, Wei
    National Center for Advancing Translational Sciences, Bethesda, Maryland, USA.
    Heilig, Markus
    Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
    A Novel Brain Penetrant NPS Receptor Antagonist, NCGC00185684, Blocks Alcohol-Induced ERK-Phosphorylation in the Central Amygdala and Decreases Operant Alcohol Self-Administration in Rats2013In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 33, no 24, p. 10132-10142Article in journal (Refereed)
    Abstract [en]

    The Neuropeptide S receptor, a Gs/Gq-coupled GPCR expressed in brain regions involved in mediating drug reward, has recently emerged as a candidate therapeutic target in addictive disorders. Here, we describe the in vitro and in vivo pharmacology of a novel, selective and brain penetrant NPSR antagonist with nanomolar affinity for the NPSR, NCGC00185684. In vitro, NCGC00185684 shows biased antagonist properties, and preferentially blocks ERK-phosphorylation over intracellular cAMP or calcium responses to NPS. In vivo, systemic NCGC00185684 blocks alcohol-induced ERK-phosphorylation in the rat central amygdala, a region involved in regulation of alcohol intake. NCGC00185684 also decreases operant alcohol self-administration, and lowers motivation for alcohol reward as measured using progressive ratio responding. These effects are behaviorally specific, in that they are observed at doses that do not influence locomotor activity or reinstatement responding following extinction. Together, these data provide an initial validation of the NPSR as a therapeutic target in alcoholism.

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