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Carlhäll, S., Källén, K., Thorsell, A. & Blomberg, M. (2018). Maternal plasma leptin levels in relation to the duration of the active phase of labor. Paper presented at 2018/09/18. Acta Obstetricia et Gynecologica Scandinavica, 97(10), 1248-1256
Öppna denna publikation i ny flik eller fönster >>Maternal plasma leptin levels in relation to the duration of the active phase of labor
2018 (Engelska)Ingår i: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 97, nr 10, s. 1248-1256Artikel i tidskrift (Refereegranskat) Published
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.

Ort, förlag, år, upplaga, sidor
Wiley-Blackwell, 2018
Nyckelord
active phase of labor, delivery, duration of labor, leptin, obesity
Nationell ämneskategori
Reproduktionsmedicin och gynekologi
Identifikatorer
urn:nbn:se:liu:diva-151340 (URN)10.1111/aogs.13380 (DOI)000444070900014 ()
Konferens
2018/09/18
Anmärkning

Funding agencies: Ostergotland County Council

Tillgänglig från: 2018-09-18 Skapad: 2018-09-18 Senast uppdaterad: 2019-04-09
Karlsson, C., Schank, J. R., Rehman, F., Stojakovic, A., Björk, K., Barbier, E., . . . Heilig, M. (2017). Proinflammatory signaling regulates voluntary alcohol intake and stress-induced consumption after exposure to social defeat stress in mice. Addiction Biology, 22(5), 1279-1288
Öppna denna publikation i ny flik eller fönster >>Proinflammatory signaling regulates voluntary alcohol intake and stress-induced consumption after exposure to social defeat stress in mice
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2017 (Engelska)Ingår i: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 22, nr 5, s. 1279-1288Artikel i tidskrift (Refereegranskat) Published
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.

Ort, förlag, år, upplaga, sidor
John Wiley & Sons, 2017
Nyckelord
CPP; IL-1RI; TNF-1R; alcohol; cytokines; social defeat stress
Nationell ämneskategori
Beroendelära
Identifikatorer
urn:nbn:se:liu:diva-146330 (URN)10.1111/adb.12416 (DOI)000408409700012 ()27273552 (PubMedID)
Tillgänglig från: 2018-04-07 Skapad: 2018-04-07 Senast uppdaterad: 2018-04-07
Karlsson, C., Rehman, F., Damdazic, R., Atkins, A. L., Schank, J. R., Gehlert, D. R., . . . Heilig, M. (2016). The melanin-concentrating hormone-1 receptor modulates alcohol-induced reward and DARPP-32 phosphorylation. Psychopharmacology, 233(12), 2355-2363
Öppna denna publikation i ny flik eller fönster >>The melanin-concentrating hormone-1 receptor modulates alcohol-induced reward and DARPP-32 phosphorylation
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2016 (Engelska)Ingår i: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, nr 12, s. 2355-2363Artikel i tidskrift (Refereegranskat) Published
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.

Ort, förlag, år, upplaga, sidor
SPRINGER, 2016
Nyckelord
Alcohol; Conditioned place preference (CPP); Knock-out mice; MCH1-R; p-DARPP-32; Reward
Nationell ämneskategori
Farmakologi och toxikologi
Identifikatorer
urn:nbn:se:liu:diva-129488 (URN)10.1007/s00213-016-4285-y (DOI)000376410800013 ()27044354 (PubMedID)
Tillgänglig från: 2016-06-21 Skapad: 2016-06-20 Senast uppdaterad: 2018-01-10
Bilbao, A., Robinson, J. E., Heilig, M., Malanga, C. J., Spanagel, R., Sommer, W. H. & Thorsell, A. (2015). A Pharmacogenetic Determinant of Mu-Opioid Receptor Antagonist Effects on Alcohol Reward and Consumption: Evidence from Humanized Mice.. Biological Psychiatry, 77(10), 850-858
Öppna denna publikation i ny flik eller fönster >>A Pharmacogenetic Determinant of Mu-Opioid Receptor Antagonist Effects on Alcohol Reward and Consumption: Evidence from Humanized Mice.
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2015 (Engelska)Ingår i: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 77, nr 10, s. 850-858Artikel i tidskrift (Refereegranskat) Published
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.

Ort, förlag, år, upplaga, sidor
Elsevier, 2015
Nationell ämneskategori
Farmakologi och toxikologi
Identifikatorer
urn:nbn:se:liu:diva-116656 (URN)10.1016/j.biopsych.2014.08.021 (DOI)000353559600004 ()25442002 (PubMedID)
Tillgänglig från: 2015-03-30 Skapad: 2015-03-30 Senast uppdaterad: 2018-01-11
Nätt, D., Johansson, I., Faresjö, T., Ludvigsson, J. & Thorsell, A. (2015). High cortisol in 5-year-old children causes loss of DNA methylation in SINE retrotransposons: a possible role for ZNF263 in stress-related diseases. Clinical Epigenetics, 7(1), Article ID 91.
Öppna denna publikation i ny flik eller fönster >>High cortisol in 5-year-old children causes loss of DNA methylation in SINE retrotransposons: a possible role for ZNF263 in stress-related diseases
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2015 (Engelska)Ingår i: Clinical Epigenetics, E-ISSN 1868-7083, ISSN 1868-7083, Vol. 7, nr 1, artikel-id 91Artikel i tidskrift (Refereegranskat) Published
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.

Ort, förlag, år, upplaga, sidor
BioMed Central, 2015
Nyckelord
Stress; DNA methylation; ZNF263; Children; Retrotransposon; Cortisol; Transcription factor; EGR1; Blood; Hair
Nationell ämneskategori
Biokemi och molekylärbiologi
Identifikatorer
urn:nbn:se:liu:diva-122055 (URN)10.1186/s13148-015-0123-z (DOI)000360619500001 ()26339299 (PubMedID)
Anmärkning

Funding Agencies|Centre for Systems Neurobiology at Linkoping University; Swedish Research Council [K2005-72X-11242-11A, K2008-69X-20826-01-4]; Swedish Child Diabetes Foundation; JDRF Wallenberg Foundation [K 98-99D-12813-01A]; Medical Research Council of Southeast Sweden (FORSS); Swedish Council for Working Life and Social Research [FAS2004-1775]

Tillgänglig från: 2015-12-18 Skapad: 2015-10-19 Senast uppdaterad: 2019-03-05
Elliott Robinson, J., Vardy, E., DiBerto, J. F., Chefer, V. I., White, K. L., Fish, E. W., . . . Malanga, C. J. (2015). Receptor Reserve Moderates Mesolimbic Responses to Opioids in a Humanized Mouse Model of the OPRM1 A118G Polymorphism. Neuropsychopharmacology, 40(11), 2614-2622
Öppna denna publikation i ny flik eller fönster >>Receptor Reserve Moderates Mesolimbic Responses to Opioids in a Humanized Mouse Model of the OPRM1 A118G Polymorphism
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2015 (Engelska)Ingår i: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 40, nr 11, s. 2614-2622Artikel i tidskrift (Refereegranskat) Published
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.

Ort, förlag, år, upplaga, sidor
NATURE PUBLISHING GROUP, 2015
Nationell ämneskategori
Klinisk medicin
Identifikatorer
urn:nbn:se:liu:diva-121737 (URN)10.1038/npp.2015.109 (DOI)000361138300014 ()25881115 (PubMedID)
Anmärkning

Funding Agencies|National Institute on Alcohol Abuse and Alcoholism [F30 AA021312, R01 AA018335]; National Institute on Drug Abuse [R01 DA017204]; Swedish Research Council [2010-3219]; intramural programs of the National Institute on Drug Abuse; NIH; Dai Nippon Sumitomo; Merck; Asubio Pharmaceuticals

Tillgänglig från: 2015-10-06 Skapad: 2015-10-05 Senast uppdaterad: 2017-12-01
Kwako, L. E., Spagnolo, P. A., Schwandt, M. L., Thorsell, A., George, D. T., Momenan, R., . . . Heilig, M. (2015). The Corticotropin Releasing Hormone-1 (CRH1) Receptor Antagonist Pexacerfont in Alcohol Dependence: A Randomized Controlled Experimental Medicine Study. Neuropsychopharmacology, 40(5), 1053-1063
Öppna denna publikation i ny flik eller fönster >>The Corticotropin Releasing Hormone-1 (CRH1) Receptor Antagonist Pexacerfont in Alcohol Dependence: A Randomized Controlled Experimental Medicine Study
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2015 (Engelska)Ingår i: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 40, nr 5, s. 1053-1063Artikel i tidskrift (Refereegranskat) Published
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.

Ort, förlag, år, upplaga, sidor
Nature Publishing Group: Open Access Hybrid Model Option A, 2015
Nationell ämneskategori
Klinisk medicin
Identifikatorer
urn:nbn:se:liu:diva-117224 (URN)10.1038/npp.2014.306 (DOI)000351022900001 ()25409596 (PubMedID)
Anmärkning

Funding Agencies|NIAAA DICBR; Cooperative Research and Development Agreement (CRADA) between the NIAAA; BristolMeyersSquibb

Tillgänglig från: 2015-04-23 Skapad: 2015-04-21 Senast uppdaterad: 2017-12-04
Holm, L., Liang, W., Thorsell, A. & Hilke, S. (2014). Acute effects on brain cholecystokinin-like concentration and anxiety-like behaviour in the female rat upon a single injection of 17β-estradiol. Pharmacology, Biochemistry and Behavior, 122, 222-227
Öppna denna publikation i ny flik eller fönster >>Acute effects on brain cholecystokinin-like concentration and anxiety-like behaviour in the female rat upon a single injection of 17β-estradiol
2014 (Engelska)Ingår i: Pharmacology, Biochemistry and Behavior, ISSN 0091-3057, E-ISSN 1873-5177, Vol. 122, s. 222-227Artikel i tidskrift (Refereegranskat) Published
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.

Ort, förlag, år, upplaga, sidor
Elsevier, 2014
Nyckelord
Anxiety, Cholecystokinin, Estrogen
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-106089 (URN)10.1016/j.pbb.2014.04.004 (DOI)000338597000025 ()24732637 (PubMedID)
Tillgänglig från: 2014-04-24 Skapad: 2014-04-24 Senast uppdaterad: 2017-12-05Bibliografiskt granskad
Cippitelli, A., Damadzic, R., Hamelink, C., Brunnquell, M., Thorsell, A., Heilig, M. & Eskay, R. L. (2014). Binge-like ethanol consumption increases corticosterone levels and neurodegneration whereas occupancy of type II glucocorticoid receptors with mifepristone is neuroprotective. Addiction Biology, 19(1), 27-36
Öppna denna publikation i ny flik eller fönster >>Binge-like ethanol consumption increases corticosterone levels and neurodegneration whereas occupancy of type II glucocorticoid receptors with mifepristone is neuroprotective
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2014 (Engelska)Ingår i: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 19, nr 1, s. 27-36Artikel i tidskrift (Refereegranskat) Published
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.

Ort, förlag, år, upplaga, sidor
Wiley-Blackwell, 2014
Nyckelord
corticosterone, ethanol, FJ-B, hippocampus, mifepristone, neurodegeneration
Nationell ämneskategori
Neurovetenskaper
Identifikatorer
urn:nbn:se:liu:diva-101831 (URN)10.1111/j.1369-1600.2012.00451.x (DOI)000328610300004 ()22500955 (PubMedID)
Tillgänglig från: 2013-11-24 Skapad: 2013-11-24 Senast uppdaterad: 2018-01-11
Thorsell, A., Tapocik, J. D., Liu, K., Zook, M., Bell, L., Flanigan, M., . . . Heilig, M. (2013). A Novel Brain Penetrant NPS Receptor Antagonist, NCGC00185684, Blocks Alcohol-Induced ERK-Phosphorylation in the Central Amygdala and Decreases Operant Alcohol Self-Administration in Rats. Journal of Neuroscience, 33(24), 10132-10142
Öppna denna publikation i ny flik eller fönster >>A Novel Brain Penetrant NPS Receptor Antagonist, NCGC00185684, Blocks Alcohol-Induced ERK-Phosphorylation in the Central Amygdala and Decreases Operant Alcohol Self-Administration in Rats
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2013 (Engelska)Ingår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 33, nr 24, s. 10132-10142Artikel i tidskrift (Refereegranskat) Published
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.

Ort, förlag, år, upplaga, sidor
Society for Neuroscience, 2013
Nyckelord
addiction, neuropeptide S, phosphorylation
Nationell ämneskategori
Neurovetenskaper
Identifikatorer
urn:nbn:se:liu:diva-94652 (URN)10.1523/JNEUROSCI.4742-12.2013 (DOI)000320235300028 ()23761908 (PubMedID)
Tillgänglig från: 2013-06-28 Skapad: 2013-06-28 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
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