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  • 51.
    Thorsell, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    The mu-Opioid Receptor and Treatment Response to Naltrexone2013In: Alcohol and Alcoholism, ISSN 0735-0414, E-ISSN 1464-3502, Vol. 48, no 4, p. 402-408Article, review/survey (Refereed)
    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.

  • 52.
    Thorsell, Annika
    et al.
    Magnus Huss Clinic, Karolinska Hospital, S-17176 Stockholm, Sweden.
    Blomqvist, Anders G
    Department of Medical Genetics, Uppsala University, Uppsala, Sweden.
    Heilig, Markus
    Magnus Huss Clinic, Karolinska Hospital, S-17176 Stockholm, Sweden.
    Cationic lipid-mediated delivery and expression of prepro-neuropeptide Y cDNA after intraventricular administration in rat: feasibility and limitations.1996In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 61, no 3, p. 205-211Article in journal (Refereed)
    Abstract [en]

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

  • 53.
    Thorsell, Annika
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Johnson, Justin
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Effect of the adenosine A2a receptor antagonist 3,7-dimethyl-propargylxanthine on anxiety-like and depression-like behavior and alcohol consumption in Wistar Rats2007In: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 31, no 8, p. 1302-1307Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 54.
    Thorsell, Annika
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Karlsson, Rose-Marie
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    NPY in alcoholism and psychiatric disorders2006In: NPY Family of Peptides in Neurobiology, Cardiovascular and Metabolic Disorders: from Genes to Therapeutics / [ed] Zofia Zukowska, Giora Z. Feuerstein, Basel: Birkhäuser Verlag, 2006, Vol. 95, p. 183-192Chapter in book (Refereed)
    Abstract [en]

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

  • 55.
    Thorsell, Annika
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Mathe, Aleksander A.
    Karolinska Institute, Sweden.
    Neuropeptide Y in Alcohol Addiction and Affective Disorders2017In: Frontiers in Endocrinology, E-ISSN 1664-2392, Vol. 8, article id 178Article, review/survey (Refereed)
    Abstract [en]

    Neuropeptide Y (NPY), a neuropeptide highly conserved throughout evolution, is present at high levels in the central nervous system (CNS), as well as in peripheral tissues such as the gut and cardiovascular system. The peptide exerts its effects via multiple receptor subtypes, all belonging to the G-protein-coupled receptor superfamily. Of these subtypes, the Y1 and the Y2 are the most thoroughly characterized, followed by the Y5 subtype. NPY and its receptors have been shown to be of importance in central regulation of events underlying, for example, affective disorders, drug/alcohol use disorders, and energy homeostasis. Furthermore, within the CNS, NPY also affects sleep regulation and circadian rhythm, memory function, tissue growth, and plasticity. The potential roles of NPY in the etiology and pathophysiology of mood and anxiety disorders, as well as alcohol use disorders, have been extensively studied. This focus was prompted by early indications for an involvement of NPY in acute responses to stress, and, later, also data pointing to a role in alterations within the CNS during chronic, or repeated, exposure to adverse events. These functions of NPY, in addition to the peptides regulation of disease states, suggest that modulation of the activity of the NPY system via receptor agonists/antagonists may be a putative treatment mechanism in affective disorders as well as alcohol use disorders. In this review, we present an overview of findings with regard to the NPY system in relation to anxiety and stress, acute as well as chronic; furthermore we discuss post-traumatic stress disorder and, in part depression. In addition, we summarize findings on alcohol use disorders and related behaviors. Finally, we briefly touch upon genetic as well as epigenetic mechanisms that may be of importance for NPY function and regulation. In conclusion, we suggest that modulation of NPY-ergic activity within the CNS, via ligands aimed at different receptor subtypes, may be attractive targets for treatment development for affective disorders, as well as for alcohol use disorders.

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  • 56.
    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 rats2007In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 130, no Pt 5, p. 1330-1337Article in journal (Refereed)
    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.

  • 57.
    Thorsell, Annika
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Schank, Jesse R.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Singley, Erick
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Hunt, Stephen P
    University College London, UK.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Neurokinin-1 receptors (NK1Rs), alcohol consumption, and alcohol reward in mice2010In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 209, no 1, p. 103-111Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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

  • 58.
    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.2005In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 161, no 1, p. 133-40Article in journal (Refereed)
    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.

  • 59.
    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 exposure2005In: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 29, no 4, p. 584-590Article in journal (Refereed)
    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.

  • 60.
    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 rats2006In: Pharmacology, Biochemistry and Behavior, ISSN 0091-3057, E-ISSN 1873-5177, Vol. 83, no 1, p. 28-34Article in journal (Refereed)
    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.

  • 61.
    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 rats2005In: Alcohol, ISSN 0741-8329, E-ISSN 1873-6823, Vol. 36, no 2, p. 91-97Article in journal (Refereed)
    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.

  • 62.
    Thorsell, Annika
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Tapocik, Jenica D
    Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
    Liu, Ke
    National Center for Advancing Translational Sciences, Bethesda, Maryland, USA.
    Zook, Michelle
    Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
    Bell, Lauren
    Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
    Flanigan, Meghan
    Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
    Patnaik, Samarjit
    National Center for Advancing Translational Sciences, Bethesda, Maryland, USA.
    Marugan, Juan
    National Center for Advancing Translational Sciences, Bethesda, Maryland, USA.
    Damadzic, Ruslan
    Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
    Dehdashti, Seameen J
    National Center for Advancing Translational Sciences, Bethesda, Maryland, USA.
    Schwandt, Melanie L
    Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
    Southall, Noel
    National Center for Advancing Translational Sciences, Bethesda, Maryland, USA.
    Austin, Christopher P
    National Center for Advancing Translational Sciences, Bethesda, Maryland, USA.
    Eskay, Robert
    Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
    Ciccocioppo, Roberto
    University of Camerino, Italy.
    Zheng, Wei
    National Center for Advancing Translational Sciences, Bethesda, Maryland, USA.
    Heilig, Markus
    Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
    A Novel Brain Penetrant NPS Receptor Antagonist, NCGC00185684, Blocks Alcohol-Induced ERK-Phosphorylation in the Central Amygdala and Decreases Operant Alcohol Self-Administration in Rats2013In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 33, no 24, p. 10132-10142Article in journal (Refereed)
    Abstract [en]

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

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