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  • 1.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Psykiatriska kliniken.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    A Pharmacogenetic Determinant of Mu-Opioid Receptor Antagonist Effects on Alcohol Reward and Consumption: Evidence from Humanized Mice.2015Ingår i: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 77, nr 10, s. 850-858Artikel i tidskrift (Refereegranskat)
    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.

  • 2.
    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 receptors2010Ingår i: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 15, nr 3, s. 299-303Artikel i tidskrift (Refereegranskat)
    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.

  • 3.
    Björk, Karl
    et al.
    Karolinska Institute, Stockholm, Sweden .
    Tronci, Valeria
    Psychobiology Section, NIDA, National Institutes of Health, Baltimore, MD, USA .
    Thorsell, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    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 alcohol2013Ingår i: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 230, nr 3, s. 439-449Artikel i tidskrift (Refereegranskat)
    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.

  • 4.
    Carlhäll, Sara
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Källén, Karin
    Institution of Clinical Sciences Lund, Center for Reproductive Epidemiology, Tornblad Institute, Lund University, Lund, Sweden.
    Thorsell, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Blomberg, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Maternal plasma leptin levels in relation to the duration of the active phase of labor2018Ingår i: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 97, nr 10, s. 1248-1256Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Abstract Introduction Obese women have increased leptin levels and longer duration of labor compared with normal-weight women. Leptin has an inhibitory effect on myometrial contractility in vitro. Our purpose was to examine whether maternal leptin levels in active labor were associated with the duration of the active phase of labor. Material and methods This prospective cohort study included 914 women. Maternal blood samples were collected in active labor. The plasma-leptin concentration was obtained using a direct sandwich-based ELISA. Bivariate and multiple linear regression analyses were used to study the association between leptin levels and the duration of labor. Results A 1 ng/mL increase in maternal plasma leptin was associated with a 0.015 hour increase in duration of labor (P < .007). This association was not statistically significant in the adjusted analyses nor when analyzing nulliparous and multiparous women separately. In women with spontaneous labor (n = 766) leptin levels were not associated with an increase in duration of labor in the adjusted analyses. Conclusions There was no significant association between leptin levels and duration of the active phase of labor. Leptin in vivo might display a similar dose-response effect on myometrial contractility as demonstrated in in vitro studies. Future studies need to explore the association between leptin levels and time in labor in obese women with high leptin levels to evaluate a possible dose-response effect.

  • 5.
    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 beyond2009Ingår i: Alcohol, ISSN 0741-8329, E-ISSN 1873-6823, Vol. 43, nr 7, s. 491-498Artikel i tidskrift (Refereegranskat)
    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.

  • 6.
    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 activation2010Ingår i: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 67, nr 9, s. 823-830Artikel i tidskrift (Refereegranskat)
    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.

  • 7.
    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 neuroprotective2014Ingår i: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 19, nr 1, s. 27-36Artikel i tidskrift (Refereegranskat)
    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.

  • 8.
    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 seeking2010Ingår i: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 208, nr 3, s. 417-426Artikel i tidskrift (Refereegranskat)
    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.

  • 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.
    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 rats2012Ingår i: Pharmacology, Biochemistry and Behavior, ISSN 0091-3057, E-ISSN 1873-5177, Vol. 100, nr 3, s. 522-529Artikel i tidskrift (Refereegranskat)
    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.

  • 10.
    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 rats2010Ingår i: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 211, nr 4, s. 367-375Artikel i tidskrift (Refereegranskat)
    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.

  • 11.
    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 anxiety2011Ingår i: Alcohol, ISSN 0741-8329, E-ISSN 1873-6823, Vol. 45, nr 6, s. 567-576Artikel i tidskrift (Refereegranskat)
    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.

  • 12.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Roth, Bryan L.
    University of N Carolina, NC 27599 USA; University of N Carolina, NC 27599 USA.
    Heilig, Markus
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Psykiatriska kliniken.
    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 Polymorphism2015Ingår i: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 40, nr 11, s. 2614-2622Artikel i tidskrift (Refereegranskat)
    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.

  • 13.
    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 alcoholism2007Ingår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 27, nr 10, s. 2718-2726Artikel i tidskrift (Refereegranskat)
    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.

  • 14.
    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 alcoholism2008Ingår i: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 319, nr 5869, s. 1536-1539Artikel i tidskrift (Refereegranskat)
    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.

  • 15.
    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 blues2010Ingår i: Neuroscience and Biobehavioral Reviews, ISSN 0149-7634, E-ISSN 1873-7528, Vol. 35, nr 2, s. 334-344Artikel i tidskrift (Refereegranskat)
    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.

  • 16.
    Holm, Lovisa
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Liang, Wen
    TNO Metabolic Health Research, Leiden, Netherlands.
    Thorsell, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Hilke, Susanne
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Acute effects on brain cholecystokinin-like concentration and anxiety-like behaviour in the female rat upon a single injection of 17β-estradiol2014Ingår i: Pharmacology, Biochemistry and Behavior, ISSN 0091-3057, E-ISSN 1873-5177, Vol. 122, s. 222-227Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: The neuropeptide cholecystokinin (CCK) has been implicated in the neurobiology of anxiety and panic disorders, as well as in dopamine-related behaviours. Anxiety and panic-disorders are twice as common in females compared to males, but studies of females are rare, although increasing in number. Limited studies have found that CCK fluctuates in limbic regions during the estrous cycle, and that CCK and its receptors are sensitive to estrogen.

    AIM/PURPOSE: The aim of the present work was to study the acute effects of 17β-estradiol on anxiety-like behaviour and on CCK-like immunoreactivity (LI) in the female rat brain (amygdala, hippocampus, nucleus accumbens, and cingulate cortex).

    METHODS: Four groups of female Sprague-Dawley rats were used: ovariectomized, ovariectomized+17β-estradiol-replacement, sham, and sham+17β-estradiol-replacement. The effect of 17β-estradiol-replacement on anxiety-related behaviour was measured in all animals on the elevated plus maze 2-24h after injection. CCK-LI concentration was measured in punch biopsies by means of radioimmunoassay.

    RESULTS: 17β-estradiol decreased anxiety-like behaviour 2h after administration in ovariectomized and sham-operated animals, as demonstrated by increased exploration of the open arms compared to respective sesame oil-treated controls. This effect was not present when testing occurred 24h post-treatment. The rapid behavioural effect of 17β-estradiol was accompanied by changes in CCK-LI concentrations in regions of the limbic system including cingulate cortex, hippocampus, amygdala and nucleus accumbens.

    CONCLUSION: Although the interpretation of these data requires caution since the data were collected from two different experiments, our results suggest that estrogen-induced anxiolytic effects may be associated with changes of the CCK-system in brain regions controlling anxiety-like behaviour.

  • 17.
    Karlsson, Camilla
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Rehman, Faazal
    NIH, MD 20892 USA.
    Damdazic, Ruslan
    NIH, MD 20892 USA.
    Atkins, Alison Lynn
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Heilig, Markus
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för social och affektiv neurovetenskap (CSAN). Region Östergötland, Närsjukvården i centrala Östergötland, Psykiatriska kliniken.
    The melanin-concentrating hormone-1 receptor modulates alcohol-induced reward and DARPP-32 phosphorylation2016Ingår i: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, nr 12, s. 2355-2363Artikel i tidskrift (Refereegranskat)
    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.

  • 18.
    Karlsson, Camilla
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Björk, Karl
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Barbier, Estelle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Thorsell, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Heilig, Markus
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Psykiatriska kliniken.
    Proinflammatory signaling regulates voluntary alcohol intake and stress-induced consumption after exposure to social defeat stress in mice2017Ingår i: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 22, nr 5, s. 1279-1288Artikel i tidskrift (Refereegranskat)
    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.

  • 19.
    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 behaviors2012Ingår i: Pharmacology, Biochemistry and Behavior, ISSN 0091-3057, E-ISSN 1873-5177, Vol. 102, nr 3, s. 400-406Artikel i tidskrift (Refereegranskat)
    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.

  • 20.
    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 mice2008Ingår i: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 195, nr 4, s. 547-557Artikel i tidskrift (Refereegranskat)
    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.

  • 21.
    Kwako, Laura E.
    et al.
    NIAAA, MD USA.
    Spagnolo, Primavera A.
    NIAAA, MD USA.
    Schwandt, Melanie L.
    NIAAA, MD USA.
    Thorsell, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    George, David T.
    NIAAA, MD USA.
    Momenan, Reza
    NIAAA, MD USA.
    Rio, Daniel E.
    NIAAA, MD USA.
    Huestis, Marilyn
    NIDA, MD USA.
    Anizan, Sebastien
    NIDA, MD USA.
    Concheiro, Marta
    NIDA, MD USA.
    Sinha, Rajrta
    Yale University, CT USA.
    Heilig, Markus
    NIAAA, MD USA.
    The Corticotropin Releasing Hormone-1 (CRH1) Receptor Antagonist Pexacerfont in Alcohol Dependence: A Randomized Controlled Experimental Medicine Study2015Ingår i: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 40, nr 5, s. 1053-1063Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Extensive preclinical data implicate corticotropin-releasing hormone (CRH), acting through its CRH1 receptor, in stress- and dependence-induced alcohol seeking. We evaluated pexacerfont, an orally available, brain penetrant CRH1 antagonist for its ability to suppress stress-induced alcohol craving and brain responses in treatment seeking alcohol-dependent patients in early abstinence. Fifty-four anxious alcohol-dependent participants were admitted to an inpatient unit at the NIH Clinical Center, completed withdrawal treatment, and were enrolled in a double-blind, randomized, placebo-controlled study with pexacerfont (300 mg/day for 7 days, followed by I 00 mg/day for 23 days). After reaching steady state, participants were assessed for alcohol craving in response to stressful or alcohol-related cues, neuroendocrine responses to these stimuli, and functional magnetic resonance imaging (fMRI) responses to alcohol-related stimuli or stimuli with positive or negative emotional valence. A separate group of 10 patients received open-label pexacerfont following the same dosing regimen and had cerebrospinal fluid sampled to estimate central nervous system exposure. Pexacerfont treatment had no effect on alcohol craving, emotional responses, or anxiety. There was no effect of pexacerfont on neural responses to alcohol-related or affective stimuli. These results were obtained despite drug levels in cerebrospinal fluid (CSF) that predict close to 90% central CRH1 receptor occupancy. CRH1 antagonists have been grouped based on their receptor dissociation kinetics, with pexacerfont falling in a category characterized by fast dissociation. Our results may indicate that antagonists with slow offset are required for therapeutic efficacy. Alternatively, the extensive preclinical data on CRH1 antagonism as a mechanism to suppress alcohol seeking may not translate to humans.

  • 22. Landén, M
    et al.
    Thorsell, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Wallin, A
    Blennow, K
    The apolipoprotein E allele epsilon 4 does not correlate with the number of senile plaques or neurofibrillary tangles in patients with Alzheimer's disease.1996Ingår i: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 61, nr 4, s. 352-256Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND AND OBJECTIVES: Apolipoprotein E (apoE) has been implicated in regenerative processes in the brain after trauma, as well as in the pathogenesis of Alzheimer's disease. Inheritance of a specific apo epsilon allele (apo epsilon 4) determines in part the risk and the mean age at onset of Alzheimer's disease. ApoE has been found to bind isoform specifically to beta-amyloid protein, the major component of senile plaques, and to the microtubule associated protein tau, which forms paired helical filaments and neurofibrillary tangles. The aim was to further examine the relation between apo epsilon alleles, especially apo epsilon 4, and the development of neuropathological changes associated with Alzheimer's disease.

    METHODS: Brains of patients with Alzheimer's disease (n = 44) and vascular dementia (n = 11) and of age matched controls (n = 29) were studied. Senile plaques and neurofibrillary tangles in the hippocampus and frontal cortex were quantified.

    RESULTS: No correlation was found between the number of apo epsilon 4 alleles and the number of senile plaques and neurofibrillary tangles in the hippocampus or the frontal cortex of patients with Alzheimer's disease, or vascular dementia, or control groups. No significant differences in duration or severity of dementia were found between patients with or. without the apo epsilon 4 allele. No increased frequency of apo epsilon 4 was found in vascular dementia. CONCLUSION AND COMMENT: Although the apo epsilon genotype clearly affects whether Alzheimer's disease will develop or not, the present study suggests that it has no influence on pathology or clinical intellectual status, once the dementia has manifested itself. No increased apo epsilon 4 allele frequency was found in neuropathologically diagnosed patients with vascular dementia in whom concomitant Alzheimer's disease can be excluded.

  • 23.
    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 neurons2011Ingår i: Anesthesiology, ISSN 0003-3022, E-ISSN 1528-1175, Vol. 115, nr 5, s. 1054-1062Artikel i tidskrift (Refereegranskat)
    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.

  • 24.
    Nätt, Daniel
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Johansson, Ingela
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Faresjö, Tomas
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Linköpings universitet, Medicinska fakulteten.
    Ludvigsson, Johnny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Thorsell, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    High cortisol in 5-year-old children causes loss of DNA methylation in SINE retrotransposons: a possible role for ZNF263 in stress-related diseases2015Ingår i: Clinical Epigenetics, E-ISSN 1868-7083, ISSN 1868-7083, Vol. 7, nr 1, artikel-id 91Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Childhood stress leads to increased risk of many adult diseases, such as major depression and cardiovascular disease. Studies show that adults with experienced childhood stress have specific epigenetic changes, but to understand the pathways that lead to disease, we also need to study the epigenetic link prospectively in children. Results: Here, we studied a homogenous group of 48 5-year-old children. By combining hair cortisol measurements (a well-documented biomarker for chronic stress), with whole-genome DNA-methylation sequencing, we show that high cortisol associates with a genome-wide decrease in DNA methylation and targets short interspersed nuclear elements (SINEs; a type of retrotransposon) and genes important for calcium transport: phenomena commonly affected in stress-related diseases and in biological aging. More importantly, we identify a zinc-finger transcription factor, ZNF263, whose binding sites where highly overrepresented in regions experiencing methylation loss. This type of zinc-finger protein has previously shown to be involved in the defense against retrotransposons. Conclusions: Our results show that stress in preschool children leads to changes in DNA methylation similar to those seen in biological aging. We suggest that this may affect future disease susceptibility by alterations in the epigenetic mechanisms that keep retrotransposons dormant. Future treatments for stress-and age-related diseases may therefore seek to target zinc-finger proteins that epigenetically control retrotransposon reactivation, such as ZNF263.

  • 25.
    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 receptor2010Ingår i: Probe Reports from the NIH Molecular Libraries Program [Internet], National Center for Biotechnology Information (US) , 2010Kapitel i bok, del av antologi (Övrigt vetenskapligt)
  • 26.
    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 Receptor2013Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 56, nr 22, s. 9045-9056Artikel i tidskrift (Refereegranskat)
    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.

  • 27.
    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 men2011Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 16, nr 8, s. 809-817Artikel i tidskrift (Refereegranskat)
    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.

  • 28.
    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 dependence2005Ingår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 375, nr 2, s. 129-133Artikel i tidskrift (Refereegranskat)
    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.

  • 29.
    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 ethanol2011Ingår i: Pharmacology, Biochemistry and Behavior, ISSN 0091-3057, E-ISSN 1873-5177, Vol. 99, nr 1, s. 7-16Artikel i tidskrift (Refereegranskat)
    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.

  • 30.
    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 antagonism2012Ingår i: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 220, nr 1, s. 215-224Artikel i tidskrift (Refereegranskat)
    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.

  • 31.
    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 anxiety2012Ingår i: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 17, nr 3, s. 634-647Artikel i tidskrift (Refereegranskat)
    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.

  • 32.
    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 L8224292011Ingår i: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 218, nr 1, s. 111-119Artikel i tidskrift (Refereegranskat)
    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.

  • 33.
    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 internalization2009Ingår i: Synapse, ISSN 0887-4476, E-ISSN 1098-2396, Vol. 63, nr 7, s. 621-624Artikel i tidskrift (Refereegranskat)
  • 34.
    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 model2010Ingår i: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 50, nr 4, s. 1402-1407Artikel i tidskrift (Refereegranskat)
    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.

  • 35.
    Slawecki, Craig J
    et al.
    The Scripps Research Institute, La Jolla, CA, USA.
    Thorsell, Annika
    The Scripps Research Institute, La Jolla, CA, USA.
    Ehlers, C L
    The Scripps Research Institute, La Jolla, CA, USA.
    Antagonism of neuropeptide YY1 receptors does not inhibit ethanol's effects on cortical EEG and ERPs in Wistar rats2005Ingår i: Journal of Studies on Alcohol, ISSN 0096-882X, E-ISSN 1934-2683, Vol. 66, nr 4, s. 559-566Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: Ethanol and neuropeptide Y (NPY) can have additive neurobehavioral effects. In the present study, the NPY Y1 receptor antagonist BIBP3226 was administered alone or in combination with a moderate dose of ethanol to determine whether it interacted with the neurobehavioral effects of ethanol.

    METHOD: Male Wistar rats were implanted with cortical recording electrodes and a lateral ventricular cannula. The effects of 1 nmol BIBP3226, 0.75 g/kg ethanol and the combination (BIBP3226 + EtOH) on neurophysiological activity and locomotion were then assessed.

    RESULTS: Ethanol significantly increased 1-2 Hz parietal cortical power and this effect was partially antagonized by BIBP3226. Peak frequencies in the parietal cortical 6-8 Hz and 8-16 Hz bands were also altered by ethanol, but these effects were not reversed by BIBP3226. BIBP3226 or ethanol, when administered alone, did not alter motor activity or cortical event-related potentials (ERPs) but administration of BIBP3226 + EtOH reduced motor activity, reduced parietal cortical N1 ERP amplitude and increased frontal cortical N1 ERP latency.

    CONCLUSIONS: In the present study, the most prominent effect of antagonizing central NPY Y1 receptors was a facilitation of the effects of ethanol. In particular, the effects of combined administration of BIBP3226 and ethanol are indicative of enhanced sedation and possibly cognitive impairment.

  • 36.
    Slawecki, Craig J.
    et al.
    The Scripps Research Institute, La Jolla, CA, USA.
    Thorsell, Annika K.
    National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, United States.
    El Khoury, Aram
    Karolinska Institute, Stockholm, Sweden.
    Mathé, Aleksander A
    Karolinska Institute, Stockholm, Sweden.
    Ehlers, Cindy L
    The Scripps Research Institute, La Jolla, CA, USA.
    Increased CRF-like and NPY-like immunoreactivity in adult rats exposed to nicotine during adolescence: relation to anxiety-like and depressive-like behavior2005Ingår i: Neuropeptides, ISSN 0143-4179, E-ISSN 1532-2785, Vol. 39, nr 4, s. 369-377Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: Recently, animal models have been developed that demonstrate that adolescent nicotine exposure produces neurobehavioral changes which persist into adulthood. This study further examined the impact of adolescent nicotine exposure on anxiety-like and depressive-like behavior, as well as on levels of corticotropin-releasing factor (CRF) and neuropeptide Y (NPY) in this model.

    METHODS: Male adolescent rats (35-40 days old) were administered nicotine using Nicoderm CQ patches (Smith-Kline Beecham). Behavior in the elevated plus maze (EPM) and forced swim test (FST) was assessed 2-3 weeks after exposure ended. Brain levels of CRF and NPY were then assessed 5-6 weeks after behavioral tests were completed. In addition, blood and brain levels of nicotine resulting from nicotine treatment were examined.

    RESULTS: After 5 days of exposure to 5 mg/kg/day nicotine, blood levels of nicotine averaged 66+/-5 ng/ml and brain nicotine levels averaged 52+/-4 ng/g. Rats exposed to nicotine displayed an anxiety-like profile in the EPM (i.e., decreased time spent in the open arms) and an antidepressant-like profile in the FST (i.e., less time spent immobile). Rats exposed to nicotine also had increased hypothalamic and frontal cortical CRF, increased hypothalamic and hippocampal NPY, and a decreased ratio of NPY to CRF in the amygdala.

    CONCLUSIONS: This study demonstrates that adolescent nicotine exposure produces lasting increases in anxiety-like behavior and may reduce depressive-like behavior. These behavioral changes also occurred in concert with alterations in CRF and NPY systems. Thus, lasting neurobehavioral changes associated with adolescent nicotine exposure may be related to allostatic changes in stress peptide systems.

  • 37.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Brain neuropeptide Y and corticotropin-releasing hormone in mediating stress and anxiety2010Ingår i: Experimental biology and medicine (Maywood, N.J.: Print), ISSN 1535-3702, E-ISSN 1535-3699, Vol. 235, nr 10, s. 1163-1167Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Neuropeptides such as neuropeptide Y (NPY) and corticotropin-releasing hormone (CRH) have been implicated not only in acute regulation of stress/anxiety-related behaviors, but adaptations and changes in these neuropeptide systems may also participate in the regulation of behavior and endocrine responses during chronic stress. NPY is an endogenous anxiolytic neuropeptide, while CRH has anxiogenic properties upon central administration. Changes in these neuropeptide systems may contribute to disease states and give us indications for putative treatment targets for stress/anxiety disorders as well as alcohol/drug dependence. In this review, we briefly present these two systems and review their involvement in mediating the responses to acute and chronic stressors, as well as their possible roles in the development and progression of stress/anxiety disorders. We suggest that neuropeptides may be attractive in treatment development for stress/anxiety disorders, as well as for alcohol/drug dependence, based on their specificity and activity following exposure to external challenges, i.e. stressors, and their differential adaptations during transition from an acute to a chronic stress exposure state.

  • 38.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Central neuropeptide Y in anxiety- and stress-related behavior and in ethanol intake2008Ingår i: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1148, s. 136-140Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    One of the most profound properties of central neuropeptide Y (NPY) is its anxiolytic, or anti-anxiety, effect. This has been demonstrated repeatedly in a number of animal models. In addition, stressors affect NPY expression in the central nervous system, with acute and repeated (chronic) stress having differential effects. Here, a brief summary of some work performed in our laboratory is presented that supports a role for NPY in regulation of stress responses and behaviors.

  • 39.
    Thorsell, Annika
    The Scripps Research Institute, La Jolla, CA, USA.
    Neuropeptide Y (NPY) in alcohol intake and dependence2007Ingår i: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 28, nr 2, s. 480-483Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Neuropeptide Y has a role in alcohol intake and dependence. NPY's effect on alcohol intake appears to be in part dependent on the individual's history of alcohol dependence. In models of high intake such as alcohol-preferring, selectively bred rat lines (e.g., the P-line and the HAD line), as well as in ethanol-vapor-exposed subjects, NPY modulates alcohol intake while leaving it unaffected during baseline conditions. The primary receptor subtype mediating NPY's effect on ethanol intake remains in question. The Y2-antagonist BIIE0246 significantly suppresses ethanol intake in an operant paradigm with a sensitization to the effect of BIIE0246 in vapor-exposed subjects. We propose the NPY system to be one of the most interesting target systems for the development of treatments for alcohol abuse and dependence.

  • 40.
    Thorsell, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    The mu-Opioid Receptor and Treatment Response to Naltrexone2013Ingår i: Alcohol and Alcoholism, ISSN 0735-0414, E-ISSN 1464-3502, Vol. 48, nr 4, s. 402-408Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    AIMS:

    To evaluate the pharmacogenetic evidence relating to the use of opioid antagonists (in particular naltrexone) in treating patients with alcohol abuse problems.

    METHODS:

    Narrative review of pre-clinical and clinical published research regarding genetic modulation of psychotropic effects produced by alcohol and the therapeutic effects of opioid antagonists.

    RESULTS:

    Alcohol activates brain reward pathways, leading to positive reinforcement of alcohol seeking and consumption. Thus, the underlying biological mechanisms may be targets for treatment, particularly in the early stages of addiction development. Alcohol reward is in part mediated by endogenous opioids. A single-nucleotide polymorphism (SNP) within the OPRM1 gene, A118G, leading to an amino acid change (Asn40Asp) in the extracellular portion of the receptor, has been implicated in alcoholism as well as in drug addiction, pain sensitivity and stress response, and in animal and human studies relates to the alcohol-dependent phenotype as well as to the treatment response to the µ-opioid antagonist naltrexone.

    CONCLUSION:

    The effect size reported in naltrexone clinical studies is often small, which may be due to heterogeneity among patients. Pharmacogenetic approaches may help guide us in the search for the appropriate treatment optimal for one patient's need.

  • 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.1996Ingår i: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 61, nr 3, s. 205-211Artikel i tidskrift (Refereegranskat)
    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 Rats2007Ingår i: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 31, nr 8, s. 1302-1307Artikel i tidskrift (Refereegranskat)
    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 disorders2006Ingår i: 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, s. 183-192Kapitel i bok, del av antologi (Refereegranskat)
    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.
    The Scripps Research Institute, La Jolla, CA, USA.
    Repunte-Canonigo, Vez
    The Scripps Research Institute, La Jolla, CA, USA.
    O'Dell, Laura E.
    The Scripps Research Institute, La Jolla, CA, USA.
    Chen, Scott A.
    The Scripps Research Institute, La Jolla, CA, USA.
    King, Alvin R.
    The Scripps Research Institute, La Jolla, CA, USA.
    Lekic, Dusan
    The Scripps Research Institute, La Jolla, CA, USA.
    Koob, George F.
    The Scripps Research Institute, La Jolla, CA, USA.
    Sanna, Pietro Paolo
    The Scripps Research Institute, La Jolla, CA, USA.
    Viral vector-induced amygdala NPY overexpression reverses increased alcohol intake caused by repeated deprivations in Wistar rats2007Ingår i: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 130, nr Pt 5, s. 1330-1337Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Acute administration of neuropeptide Y (NPY) modulates alcohol intake in genetic and chemical models of high intake, while leaving intake unaffected during 'normal' or baseline conditions. In non-selected, normal rat lines, alcohol consumption can be increased by prolonged exposure to alcohol, and it is unclear what effect a constitutive increase in NPY function will have on alcohol intake. The purpose of the present study was to examine the effects on alcohol intake of an inducible, constitutive overexpression of NPY, one of the most abundant neuropeptides in the central nervous system. A liquid diet was used in combination with repeated alcohol deprivation sessions to increase alcohol intake in normal Wistar rats. We then examined the effect of NPY overexpression in the amygdala on excessive alcohol intake produced by prolonged exposure to alcohol and alcohol deprivation. Repeated withdrawal increased alcohol consumption in a 24-h continuous access two-bottle choice model. Both the number of withdrawals as well as the length of the withdrawal periods affected alcohol consumption with an increased intake resulting from multiple withdrawals and the alcohol deprivation effect being enhanced by longer periods of abstinence. The increase in intake following repeated abstinence was blunted by intra-amygdala administration of a Sindbis viral vector containing NPY cDNA. Amygdala NPY overexpression also was demonstrated to be anxiolytic in the open field test. Repeated withdrawal in combination with a history of alcohol consumption significantly elevated alcohol intake, and the amygdala may mediate the transition to high-drinking states in this model.

  • 45.
    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 mice2010Ingår i: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 209, nr 1, s. 103-111Artikel i tidskrift (Refereegranskat)
    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.

  • 46.
    Thorsell, Annika
    et al.
    The Scripps Research Institute, La Jolla, CA, USA.
    Slawecki, Craig J
    The Scripps Research Institute, La Jolla, CA, USA.
    Ehlers, Cindy L
    The Scripps Research Institute, La Jolla, CA, USA.
    Effects of neuropeptide Y and corticotropin-releasing factor on ethanol intake in Wistar rats: interaction with chronic ethanol exposure.2005Ingår i: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 161, nr 1, s. 133-40Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Neuropeptide Y (NPY) and corticotropin-releasing factor (CRF) have opposing effects on stress-associated and consummatory behaviors in rodents. Recent studies also suggest that both peptides influence ethanol intake. In the present study, the effects of administration of CRF and NPY into the lateral ventricle on ethanol intake in naive and ethanol-vapor-exposed Wistar rats were examined. A limited access paradigm was used to measure intake of a 10% (v/v) ethanol solution in Wistar rats trained to drink using a sucrose fading procedure. Ethanol vapor exposure for 8 weeks significantly elevated ethanol intake in this limited access paradigm relative to pre-exposure levels. The effects of icv administration of CRF (1 microg), NPY (10 microg) or NPY/CRF combined (10 and 1 microg, respectively) on ethanol intake were then assessed. In non-vapor-exposed subjects, icv infusion of NPY had no effect on ethanol intake, while a significant suppression of drinking was seen following icv administration of CRF. Administration of NPY in combination with CRF had no effect on ethanol intake in non-ethanol-vapor-exposed rats. In vapor-exposed subjects, both NPY and CRF reduced ethanol intake, but when given in combination, no difference from vehicle was detected. Locomotor activity was measured during drinking sessions and was unaffected by peptide administration. These studies underscore the importance of a history of exposure to chronic ethanol vapor in the regulation of ethanol intake by NPY. Furthermore, the results presented here suggest that a balance between the stress-related peptides NPY and CRF may be involved in the regulation of ethanol intake.

  • 47.
    Thorsell, Annika
    et al.
    The Scripps Research Institute, La Jolla, CA, USA.
    Slawecki, Craig J.
    The Scripps Research Institute, La Jolla, CA, USA.
    Ehlers, Cindy L.
    The Scripps Research Institute, La Jolla, CA, USA.
    Effects of neuropeptide Y on appetitive and consummatory behaviors associated with alcohol drinking in wistar rats with a history of ethanol exposure2005Ingår i: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 29, nr 4, s. 584-590Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Neuropeptide Y (NPY) reduces ethanol intake under free access conditions in Wistar rats with a history of prolonged ethanol vapor exposure. The current study was designed to determine whether NPY differentially alters ethanol-associated appetitive behavior (i.e., lever pressing) or ethanol consumption in Wistar rats with a history of ethanol vapor exposure.

    METHODS: Wistar rats were first trained to self-administer 10% ethanol in a paradigm that provided 25 min of free access to 10% ethanol after completing a 20-lever press response requirement (i.e., an RR20 schedule). After stable level lever pressing was established, operant sessions were suspended during a 9-week period of ethanol vapor exposure. Self-administration sessions were then reinstituted, and a fixed time (FT) schedule of 10% ethanol access was used to assess the effects of ethanol exposure and NPY on lever pressing and drinking behavior. Under the FT schedule, the maximum number of lever presses emitted within 10 min was assessed before providing access to 10% ethanol.

    RESULTS: Ethanol vapor exposure did not alter patterns of lever pressing under the RR20 schedule, but lever presses emitted under the FT schedule were reduced after ethanol vapor exposure. Ethanol intake was significantly increased after ethanol vapor exposure. NPY significantly reduced ethanol intake but did not significantly reduce lever pressing under the FT schedule.

    CONCLUSIONS: Taken together, these data suggest that chronic ethanol exposure increases ethanol intake without clearly enhancing its reinforcing value. Furthermore, NPY has a greater impact on the consummatory factors mediating ethanol intake than appetitive factors mediating ethanol seeking.

  • 48.
    Thorsell, Annika
    et al.
    The Scripps Research Institute, La Jolla, CA, USA.
    Slawecki, Craig J.
    The Scripps Research Institute, La Jolla, CA, USA.
    El Khoury, Aram
    Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden.
    Mathe, Aleksander A.
    Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden.
    Ehlers, Cindy L.
    The Scripps Research Institute, La Jolla, CA, USA.
    The effects of social isolation on neuropeptide Y levels, exploratory and anxiety-related behaviors in rats2006Ingår i: Pharmacology, Biochemistry and Behavior, ISSN 0091-3057, E-ISSN 1873-5177, Vol. 83, nr 1, s. 28-34Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    NPY is one of the most abundantly expressed peptides within the CNS, and has been previously demonstrated to be altered in several animal models of depression, as well as to be differentially regulated by acute and repeated stress. The effect of social deprivation, through isolation housing, on brain NPY concentrations in adult rats has not been previously investigated. The effects of 12 weeks of social isolation, in adult rats, on anxiety-related behaviors and central concentrations of NPY in: hypothalamus, amygdala, caudate-putamen, hippocampus, and frontal cortex were evaluated. Single housed animals spent significantly more time on the open arms of the elevated plus maze and in the central area of the open field as compared to pair housed controls. These data are most likely indicative of enhanced exploration and novelty seeking. Concentrations of neuropeptide Y were increased in the caudate-putamen of the single housed subjects. NPY levels in caudate/putamen and hypothalamus were also significantly correlated with time spent in the open arms of the elevated plus maze. These data suggest that chronic social isolation, in these adult Wistar rats, did not increase anxiety but produced enhanced exploration in tests of anxiety, an effect that was associated with NPY concentrations in the striatum and hypothalamus.

  • 49.
    Thorsell, Annika
    et al.
    The Scripps Research Institute, La Jolla, CA, USA.
    Slawecki, Craig J.
    The Scripps Research Institute, La Jolla, CA, USA.
    Khoury, Aram
    Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden.
    Mathe, Aleksander A.
    Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden.
    Ehlers, Cindy L.
    The Scripps Research Institute, La Jolla, CA, USA.
    Effect of social isolation on ethanol consumption and substance P/neurokinin expression in Wistar rats2005Ingår i: Alcohol, ISSN 0741-8329, E-ISSN 1873-6823, Vol. 36, nr 2, s. 91-97Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Environmental factors, such as adverse life experiences and family/peer influences have a substantial influence on the development of disorders related to alcohol use. In animals, maternal or peer separation/isolation has been used as an environmental intervention that has been shown to alter neurodevelopment and influence drinking behaviors in rodents and primates. In this study, the effects of adult peer isolation on subsequent ethanol intake were investigated in Wistar rats. Because central tachykinin levels have been reported to differ between rats selected for enhanced ethanol preference, neuropeptide [neurokinin A (NKA), substance P (SP)] concentrations were also estimated. Lower levels of ethanol intake, in a two-bottle free-choice model, were observed on the first day of forced ethanol drinking in the single-housed animals. However, overall ethanol consumption was unaffected by peer isolation. Peer isolation significantly lowered SP and NKA levels in the hypothalamus, but this effect was not related to ethanol consumption or body weight. These data indicate that endogenous SP and neurokinin levels are reduced by isolation housing, but this was not associated with alterations in drinking levels using a two-bottle choice procedure.

  • 50.
    Thorsell, Annika
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    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 Rats2013Ingår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 33, nr 24, s. 10132-10142Artikel i tidskrift (Refereegranskat)
    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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