Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

NOP receptor antagonism attenuates reinstatement of alcohol-seeking through modulation of the mesolimbic circuitry in male and female alcohol-preferring rats


In patients suffering from alcohol use disorder (AUD), stress and environmental stimuli associated with alcohol availability are important triggers of relapse. Activation of the nociceptin opioid peptide (NOP) receptor by its endogenous ligand Nociceptin/Orphanin FQ (N/OFQ) attenuates alcohol drinking and relapse in rodents, suggesting that NOP agonists may be efficacious in treating AUD. Intriguingly, recent data demonstrated that also blockade of NOP receptor reduced alcohol drinking in rodents. To explore further the potential of NOP antagonism, we investigated its effects on the reinstatement of alcohol-seeking elicited by administration of the α2 antagonist yohimbine (1.25 mg/kg, i.p.) or by environmental conditioning factors in male and female genetically selected alcohol-preferring Marchigian Sardinian (msP) rats. The selective NOP receptor antagonist LY2817412 (0.0, 3.0, 10.0, and 30.0 mg/kg) was first tested following oral (p.o.) administration. We then investigated the effects of LY2817412 (1.0, 3.0, 6.0 μg/μl/rat) microinjected into three candidate mesolimbic brain regions: the ventral tegmental area (VTA), the central nucleus of the amygdala (CeA), and the nucleus accumbens (NAc). We found that relapse to alcohol seeking was generally stronger in female than in male rats and oral administration of LY2817412 reduced yohimbine- and cue-induced reinstatement in both sexes. Following site-specific microinjections, LY2817412 reduced yohimbine-induced reinstatement of alcohol-seeking when administered into the VTA and the CeA, but not in the NAc. Cue-induced reinstatement was suppressed only when LY2817412 was microinjected into the VTA. Infusions of LY2817412 into the VTA and the CeA did not alter saccharin self-administration. These results demonstrate that NOP receptor blockade prevents the reinstatement of alcohol-seeking through modulation of mesolimbic system circuitry, providing further evidence of the therapeutic potential of NOP receptor antagonism in AUD.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Effect of Systemic Administration of LY2817412 on Yohimbine-Induced Reinstatement of Alcohol Seeking in Male and Female msP Rats.
Fig. 2: Effect of Systemic Administration of LY2817412 on Cue-Induced Reinstatement of Alcohol-Seeking in Male and Female msP Rats.
Fig. 3: Effect of Intra-VTA, Intra-CeA and Intra-NAc Administration of LY2817412 on Yohimbine‐Induced Reinstatement of Alcohol Seeking in Male and Female msP rats.
Fig. 4: Effect of Intra-VTA, Intra-CeA and Intra-NAc Administration of LY2817412 on Cue‐Induced Reinstatement of Alcohol Seeking in Male and Female msP rats.
Fig. 5: Effect of Intra-VTA and Intra-CeA Administration of LY2817412 on Saccharin Self-Administration in Male and Female msP rats.


  1. 1.

    Koob GF. Neurocircuitry of alcohol addiction: synthesis from animal models. Handb Clin Neurol. 2014;125:33–54.

    PubMed  Google Scholar 

  2. 2.

    Koob GF, Le Moal M. Plasticity of reward neurocircuitry and the ‘dark side’ of drug addiction. Nat Neurosci. 2005;8:1442–4.

    PubMed  CAS  Google Scholar 

  3. 3.

    Monti PM, Binkoff JA, Abrams DB, Zwick WR, Nirenberg TD, Liepman MR. Reactivity of alcoholics and nonalcoholics to drinking cues. J Abnorm Psychol. 1987;96:122–6.

    PubMed  CAS  Google Scholar 

  4. 4.

    Martin-Fardon R, Weiss F. Modeling relapse in animals. Curr Top Behav Neurosci. 2013;13:403–32.

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Cooney NL, Litt MD, Morse PA, Bauer LO, Gaupp L. Alcohol cue reactivity, negative-mood reactivity, and relapse in treated alcoholic men. J Abnorm Psychol. 1997;106:243–50.

    PubMed  CAS  Google Scholar 

  6. 6.

    Goldstein RZ, Craig AD, Bechara A, Garavan H, Childress AR, Paulus MP, et al. The neurocircuitry of impaired insight in drug addiction. Trends Cogn Sci. 2009;13:372–80.

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Zilverstand A, Huang AS, Alia-Klein N, Goldstein RZ. Neuroimaging Impaired Response Inhibition and Salience Attribution in Human Drug Addiction: a Systematic Review. Neuron. 2018;98:886–903.

    PubMed  PubMed Central  CAS  Google Scholar 

  8. 8.

    Reinscheid RK, Nothacker HP, Bourson A, Ardati A, Henningsen RA, Bunzow JR, et al. Orphanin FQ: a neuropeptide that activates an opioidlike G protein-coupled receptor. Science. 1995;270:792–4.

    PubMed  CAS  Google Scholar 

  9. 9.

    Meunier JC, Mollereau C, Toll L, Suaudeau C, Moisand C, Alvinerie P, et al. Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor. Nature. 1995;377:532–5.

    PubMed  CAS  Google Scholar 

  10. 10.

    Ciccocioppo R, Borruto AM, Domi A, Teshima K, Cannella N, Weiss F. NOP-Related Mechanisms in Substance Use Disorders. Handb Exp Pharm. 2019;254:187–212.

    CAS  Google Scholar 

  11. 11.

    Zaveri NT. Nociceptin Opioid Receptor (NOP) as a Therapeutic Target: progress in Translation from Preclinical Research to Clinical Utility. J Med Chem. 2016;59:7011–28.

    PubMed  PubMed Central  CAS  Google Scholar 

  12. 12.

    Witkin JM, Statnick MA, Rorick-Kehn LM, Pintar JE, Ansonoff M, Chen Y, et al. The biology of Nociceptin/Orphanin FQ (N/OFQ) related to obesity, stress, anxiety, mood, and drug dependence. Pharm Ther. 2014;141:283–99.

    CAS  Google Scholar 

  13. 13.

    Ciccocioppo R, Economidou D, Fedeli A, Angeletti S, Weiss F, Heilig M, et al. Attenuation of ethanol self-administration and of conditioned reinstatement of alcohol-seeking behaviour by the antiopioid peptide nociceptin/orphanin FQ in alcohol-preferring rats. Psychopharmacol (Berl). 2004;172:170–8.

    CAS  Google Scholar 

  14. 14.

    Martin-Fardon R, Ciccocioppo R, Massi M, Weiss F. Nociceptin prevents stress-induced ethanol- but not cocaine-seeking behavior in rats. Neuroreport. 2000;11:1939–43.

    PubMed  CAS  Google Scholar 

  15. 15.

    de Guglielmo G, Martin-Fardon R, Teshima K, Ciccocioppo R, Weiss F. MT-7716, a potent NOP receptor agonist, preferentially reduces ethanol seeking and reinforcement in post-dependent rats. Addict Biol. 2015;20:643–51.

    PubMed  Google Scholar 

  16. 16.

    Rorick-Kehn LM, Ciccocioppo R, Wong CJ, Witkin JM, Martinez-Grau MA, Stopponi S, et al. A Novel, Orally Bioavailable Nociceptin Receptor Antagonist, LY2940094, Reduces Ethanol Self-Administration and Ethanol Seeking in Animal Models. Alcohol Clin Exp Res. 2016;40:945–54.

    PubMed  PubMed Central  CAS  Google Scholar 

  17. 17.

    Borruto AM, Fotio Y, Stopponi S, Brunori G, Petrella M, Caputi FF, et al. NOP receptor antagonism reduces alcohol drinking in male and female rats through mechanisms involving the central amygdala and ventral tegmental area. Br J Pharm. 2020;177:1525–37.

    CAS  Google Scholar 

  18. 18.

    Brunori G, Weger M, Schoch J, Targowska-Duda K, Barnes M, Borruto AM, et al. NOP Receptor Antagonists Decrease Alcohol Drinking in the Dark in C57BL/6J Mice. Alcohol Clin Exp Res. 2019;43:2167–78.

    PubMed  PubMed Central  CAS  Google Scholar 

  19. 19.

    Cippitelli A, Schoch J, Debevec G, Brunori G, Zaveri NT, Toll L. A key role for the N/OFQ-NOP receptor system in modulating nicotine taking in a model of nicotine and alcohol co-administration. Sci Rep. 2016;6:26594.

    PubMed  PubMed Central  CAS  Google Scholar 

  20. 20.

    Neal CR Jr, Mansour A, Reinscheid R, Nothacker HP, Civelli O, Watson SJ Jr. Localization of orphanin FQ (nociceptin) peptide and messenger RNA in the central nervous system of the rat. J Comp Neurol. 1999;406:503–47.

    PubMed  CAS  Google Scholar 

  21. 21.

    Letchworth SR, Mathis JP, Rossi GC, Bodnar RJ, Pasternak GW. Autoradiographic localization of (125)I[Tyr(14)]orphanin FQ/nociceptin and (125)I[Tyr(10)]orphanin FQ/nociceptin(1-11) binding sites in rat brain. J Comp Neurol. 2000;423:319–29.

    PubMed  CAS  Google Scholar 

  22. 22.

    Economidou D, Mattioli L, Cifani C, Perfumi M, Massi M, Cuomo V, et al. Effect of the cannabinoid CB1 receptor antagonist SR-141716A on ethanol self-administration and ethanol-seeking behaviour in rats. Psychopharmacol (Berl). 2006;183:394–403.

    CAS  Google Scholar 

  23. 23.

    Toledo MA, Pedregal C, Lafuente C, Diaz N, Martinez-Grau MA, Jiménez A, et al. Discovery of a novel series of orally active nociceptin/orphanin FQ (NOP) receptor antagonists based on a dihydrospiro(piperidine-4,7’-thieno[2,3-c]pyran) scaffold. J Med Chem. 2014;57:3418–29.

    PubMed  CAS  Google Scholar 

  24. 24.

    Ciccocioppo R, Stopponi S, Economidou D, Kuriyama M, Kinoshita H, Heilig M, et al. Chronic treatment with novel brain-penetrating selective NOP receptor agonist MT-7716 reduces alcohol drinking and seeking in the rat. Neuropsychopharmacology. 2014;39:2601–10.

    PubMed  PubMed Central  CAS  Google Scholar 

  25. 25.

    Ciccocioppo R, Martin-Fardon R, Weiss F, Massi M. Nociceptin/orphanin FQ inhibits stress- and CRF-induced anorexia in rats. Neuroreport. 2001;12:1145–9.

    PubMed  CAS  Google Scholar 

  26. 26.

    Ciccocioppo R, Biondini M, Antonelli L, Wichmann J, Jenck F, Massi M. Reversal of stress- and CRF-induced anorexia in rats by the synthetic nociceptin/orphanin FQ receptor agonist, Ro 64-6198. Psychopharmacol (Berl). 2002;161:113–9.

    CAS  Google Scholar 

  27. 27.

    Aziz AM, Brothers S, Sartor G, Holm L, Heilig M, Wahlestedt C, et al. The nociceptin/orphanin FQ receptor agonist SR-8993 as a candidate therapeutic for alcohol use disorders: validation in rat models. Psychopharmacol (Berl). 2016;233:3553–63.

    CAS  Google Scholar 

  28. 28.

    Mantsch JR, Baker DA, Funk D, Lê AD, Shaham Y. Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress. Neuropsychopharmacology. 2016;41:335–56.

    PubMed  CAS  Google Scholar 

  29. 29.

    Namba MD, Tomek SE, Olive MF, Beckmann JS, Gipson CD. The Winding Road to Relapse: forging a New Understanding of Cue-Induced Reinstatement Models and Their Associated Neural Mechanisms. Front Behav Neurosci. 2018;12:17.

    PubMed  PubMed Central  Google Scholar 

  30. 30.

    Norton CS, Neal CR, Kumar S, Akil H, Watson SJ. Nociceptin/orphanin FQ and opioid receptor-like receptor mRNA expression in dopamine systems. J Comp Neurol. 2002;444:358–68.

    PubMed  CAS  Google Scholar 

  31. 31.

    Zheng F, Grandy DK, Johnson SW. Actions of orphanin FQ/nociceptin on rat ventral tegmental area neurons in vitro. Br J Pharm. 2002;136:1065–71.

    CAS  Google Scholar 

  32. 32.

    Murphy NP, Maidment NT. Orphanin FQ/nociceptin modulation of mesolimbic dopamine transmission determined by microdialysis. J Neurochem. 1999;73:179–86.

    PubMed  CAS  Google Scholar 

  33. 33.

    Lutfy K, Do T, Maidment NT. Orphanin FQ/nociceptin attenuates motor stimulation and changes in nucleus accumbens extracellular dopamine induced by cocaine in rats. Psychopharmacol (Berl). 2001;154:1–7.

    CAS  Google Scholar 

  34. 34.

    Di Giannuario A, Pieretti S. Nociceptin differentially affects morphine-induced dopamine release from the nucleus accumbens and nucleus caudate in rats. Peptides. 2000;21:1125–30.

    PubMed  Google Scholar 

  35. 35.

    Vazquez-DeRose J, Stauber G, Khroyan TV, Xie XS, Zaveri NT, Toll L. Retrodialysis of N/OFQ into the nucleus accumbens shell blocks cocaine-induced increases in extracellular dopamine and locomotor activity. Eur J Pharm. 2013;699:200–6.

    CAS  Google Scholar 

  36. 36.

    Brodie MS, Scholz A, Weiger TM, Dopico AM. Ethanol interactions with calcium-dependent potassium channels. Alcohol Clin Exp Res. 2007;31:1625–32.

    PubMed  CAS  Google Scholar 

  37. 37.

    Budygin EA, Bass CE, Grinevich VP, Deal AL, Bonin KD, Weiner JL. Opposite Consequences of Tonic and Phasic Increases in Accumbal Dopamine on Alcohol-Seeking Behavior. iScience. 2020;23:100877.

    PubMed  PubMed Central  CAS  Google Scholar 

  38. 38.

    You C, Vandegrift B, Brodie MS. Ethanol actions on the ventral tegmental area: novel potential targets on reward pathway neurons. Psychopharmacol (Berl). 2018;235:1711–26.

    CAS  Google Scholar 

  39. 39.

    Toll L, Bruchas MR, Calo' G, Cox BM, Zaveri NT. Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems. Pharm Rev. 2016;68:419–57.

    PubMed  PubMed Central  Google Scholar 

  40. 40.

    Driscoll, JR, Wallace TL, Mansourian KA, Martin WJ, Margolis EB. Differential Modulation of Ventral Tegmental Area Circuits by the Nociceptin/Orphanin FQ System. eNeuro. 2020;7:1–15.

    Google Scholar 

  41. 41.

    Umhau JC, Schwandt ML, Usala J, Geyer C, Singley E, George DT, et al. Pharmacologically induced alcohol craving in treatment seeking alcoholics correlates with alcoholism severity, but is insensitive to acamprosate. Neuropsychopharmacology. 2011;36:1178–86.

    PubMed  PubMed Central  CAS  Google Scholar 

  42. 42.

    Simms JA, Bito-Onon JJ, Chatterjee S, Bartlett SE. Long-Evans rats acquire operant self-administration of 20% ethanol without sucrose fading. Neuropsychopharmacology. 2010;35:1453–63.

    PubMed  PubMed Central  CAS  Google Scholar 

  43. 43.

    Lê AD, Funk D, Coen K, Li Z, Shaham Y. Role of corticotropin-releasing factor in the median raphe nucleus in yohimbine-induced reinstatement of alcohol seeking in rats. Addict Biol. 2013;18:448–51.

    PubMed  Google Scholar 

  44. 44.

    Richards JK, Simms JA, Steensland P, Taha SA, Borgland SL, Bonci A, et al. Inhibition of orexin-1/hypocretin-1 receptors inhibits yohimbine-induced reinstatement of ethanol and sucrose seeking in Long-Evans rats. Psychopharmacol (Berl). 2008;199:109–17.

    CAS  Google Scholar 

  45. 45.

    Cippitelli A, Damadzic R, Hansson AC, Singley E, Sommer WH, Eskay R, et al. Neuropeptide Y (NPY) suppresses yohimbine-induced reinstatement of alcohol seeking. Psychopharmacol (Berl). 2010;208:417–26.

    CAS  Google Scholar 

  46. 46.

    Bossert JM, Marchant NJ, Calu DJ, Shaham Y. The reinstatement model of drug relapse: recent neurobiological findings, emerging research topics, and translational research. Psychopharmacol (Berl). 2013;229:453–76.

    CAS  Google Scholar 

  47. 47.

    Chen YW, Fiscella KA, Bacharach SZ, Tanda G, Shaham Y, Calu DJ. Effect of yohimbine on reinstatement of operant responding in rats is dependent on cue contingency but not food reward history. Addict Biol. 2015;20:690–700.

    PubMed  CAS  Google Scholar 

  48. 48.

    Tabbara RI, Rahbarnia A, Lê AD, Fletcher PJ. The pharmacological stressor yohimbine, but not U50,488, increases responding for conditioned reinforcers paired with ethanol or sucrose. Psychopharmacol (Berl). 2020;237:3689–702.

    CAS  Google Scholar 

  49. 49.

    Mahler SV, Moorman DE, Feltenstein MW, Cox BM, Ogburn KB, Bachar M, et al. A rodent “self-report” measure of methamphetamine craving? Rat ultrasonic vocalizations during methamphetamine self-administration, extinction, and reinstatement. Behav Brain Res. 2013;236:78–89.

    PubMed  CAS  Google Scholar 

  50. 50.

    Ball KT, Miller L, Sullivan C, Wells A, Best O, Cavanaugh B, et al. Effects of repeated yohimbine administration on reinstatement of palatable food seeking: involvement of dopamine D1 -like receptors and food-associated cues. Addict Biol. 2016;21:1140–50.

    PubMed  CAS  Google Scholar 

  51. 51.

    Brown ZJ, Kupferschmidt DA, Erb S. Reinstatement of cocaine seeking in rats by the pharmacological stressors, corticotropin-releasing factor and yohimbine: role for D1/5 dopamine receptors. Psychopharmacol (Berl). 2012;224:431–40.

    CAS  Google Scholar 

  52. 52.

    Nair SG, Navarre BM, Cifani C, Pickens CL, Bossert JM, Shaham Y. Role of dorsal medial prefrontal cortex dopamine D1-family receptors in relapse to high-fat food seeking induced by the anxiogenic drug yohimbine. Neuropsychopharmacology. 2011;36:497–510.

    PubMed  CAS  Google Scholar 

  53. 53.

    Koob GF. Brain stress systems in the amygdala and addiction. Brain Res. 2009;1293:61–75.

    PubMed  PubMed Central  CAS  Google Scholar 

  54. 54.

    Becker HC. Effects of alcohol dependence and withdrawal on stress responsiveness and alcohol consumption. Alcohol Res. 2012;34:448–58.

    PubMed  PubMed Central  Google Scholar 

  55. 55.

    Jenck F, Moreau JL, Martin JR, Kilpatrick GJ, Reinscheid RK, Monsma FJ Jr, et al. Orphanin FQ acts as an anxiolytic to attenuate behavioral responses to stress. Proc Natl Acad Sci USA. 1997;94:14854–8.

    PubMed  PubMed Central  CAS  Google Scholar 

  56. 56.

    Jenck F, Ouagazzal AM, Pauly-Evers M, Moreau JL. OrphaninFQ: role in behavioral fear responses and vulnerability to stress? Mol Psychiatry. 2000;5:572–4.

    PubMed  CAS  Google Scholar 

  57. 57.

    Ciccocioppo R, de Guglielmo G, Hansson AC, Ubaldi M, Kallupi M, Cruz MT, et al. Restraint stress alters nociceptin/orphanin FQ and CRF systems in the rat central amygdala: significance for anxiety-like behaviors. J Neurosci. 2014;34:363–72.

    PubMed  PubMed Central  CAS  Google Scholar 

  58. 58.

    Andero R, Brothers SP, Jovanovic T, Chen YT, Salah-Uddin H, Cameron M, et al. Amygdala-dependent fear is regulated by Oprl1 in mice and humans with PTSD. Sci Transl Med. 2013;5:188ra73.

    PubMed  PubMed Central  Google Scholar 

  59. 59.

    Gavioli EC, Holanda VAD, Ruzza C. NOP Ligands for the Treatment of Anxiety and Mood Disorders. Handb Exp Pharm. 2019;254:233–57.

    CAS  Google Scholar 

  60. 60.

    Witkin JM, Rorick-Kehn LM, Benvenga MJ, Adams BL, Gleason SD, Knitowski KM, et al. Preclinical findings predicting efficacy and side-effect profile of LY2940094, an antagonist of nociceptin receptors. Pharm Res Perspect. 2016;4:e00275.

    Google Scholar 

  61. 61.

    Duzzioni M, Duarte FS, Leme LR, Gavioli EC, De Lima TC. Anxiolytic-like effect of central administration of NOP receptor antagonist UFP-101 in rats submitted to the elevated T-maze. Behav Brain Res. 2011;222:206–11.

    PubMed  CAS  Google Scholar 

  62. 62.

    Post A, Smart TS, Krikke-Workel J, Dawson GR, Harmer CJ, Browning M, et al. A Selective Nociceptin Receptor Antagonist to Treat Depression: evidence from Preclinical and Clinical Studies. Neuropsychopharmacology. 2016;41:1803–12.

    PubMed  CAS  Google Scholar 

  63. 63.

    Genovese RF, Dobre S. Mitigation of adverse behavioral impact from predator exposure by the nociceptin/orphanin FQ peptide antagonist J-113397 in rats. Behav Pharm. 2017;28:521–30.

    CAS  Google Scholar 

  64. 64.

    Zhang Y, Schalo I, Durand C, Standifer KM. Sex Differences in Nociceptin/Orphanin FQ Peptide Receptor-Mediated Pain and Anxiety Symptoms in a Preclinical Model of Post-traumatic Stress Disorder. Front Psychiatry. 2018;9:731.

    PubMed  CAS  Google Scholar 

  65. 65.

    Silva AI, Holanda V, Azevedo Neto JG, Silva Junior ED, Soares-Rachetti VP, Calo G, et al. Blockade of NOP receptor modulates anxiety-related behaviors in mice exposed to inescapable stress. Psychopharmacol (Berl). 2020;237:1633–42.

    CAS  Google Scholar 

  66. 66.

    Hansson AC, Cippitelli A, Sommer WH, Fedeli A, Björk K, Soverchia L, et al. Variation at the rat Crhr1 locus and sensitivity to relapse into alcohol seeking induced by environmental stress. Proc Natl Acad Sci USA. 2006;103:15236–41.

    PubMed  PubMed Central  CAS  Google Scholar 

  67. 67.

    Hansson AC, Cippitelli A, Sommer WH, Ciccocioppo R, Heilig M. Region-specific down-regulation of Crhr1 gene expression in alcohol-preferring msP rats following ad lib access to alcohol. Addict Biol. 2007;12:30–4.

    PubMed  CAS  Google Scholar 

  68. 68.

    Economidou D, Hansson AC, Weiss F, Terasmaa A, Sommer WH, Cippitelli A, et al. Dysregulation of nociceptin/orphanin FQ activity in the amygdala is linked to excessive alcohol drinking in the rat. Biol Psychiatry. 2008;64:211–8.

    PubMed  PubMed Central  CAS  Google Scholar 

  69. 69.

    Ciccocioppo R, Economidou D, Cippitelli A, Cucculelli M, Ubaldi M, Soverchia L, et al. Genetically selected Marchigian Sardinian alcohol-preferring (msP) rats: an animal model to study the neurobiology of alcoholism. Addict Biol. 2006;11:339–55.

    PubMed  PubMed Central  Google Scholar 

  70. 70.

    Borruto, AM, Stopponi S, Li H, Weiss F, Roberto M, Ciccocioppo R, et al., Genetically Selected Alcohol-Preferring msP Rats to Study Alcohol Use Disorder: Anything Lost in Translation? Neuropharmacology. 2021;186:108446.

    PubMed  CAS  Google Scholar 

  71. 71.

    Roberto M, Siggins GR. Nociceptin/orphanin FQ presynaptically decreases GABAergic transmission and blocks the ethanol-induced increase of GABA release in central amygdala. Proc Natl Acad Sci USA. 2006;103:9715–20.

    PubMed  PubMed Central  CAS  Google Scholar 

  72. 72.

    Cruz MT, Herman MA, Kallupi M, Roberto M. Nociceptin/orphanin FQ blockade of corticotropin-releasing factor-induced gamma-aminobutyric acid release in central amygdala is enhanced after chronic ethanol exposure. Biol Psychiatry. 2012;71:666–76.

    PubMed  CAS  Google Scholar 

  73. 73.

    Kallupi M, Varodayan FP, Oleata CS, Correia D, Luu G, Roberto M. Nociceptin/orphanin FQ decreases glutamate transmission and blocks ethanol-induced effects in the central amygdala of naive and ethanol-dependent rats. Neuropsychopharmacology. 2014;39:1081–92.

    PubMed  CAS  Google Scholar 

  74. 74.

    Chieng B, Christie MJ. Somatostatin and nociceptin inhibit neurons in the central nucleus of amygdala that project to the periaqueductal grey. Neuropharmacology. 2010;59:425–30.

    PubMed  CAS  Google Scholar 

  75. 75.

    Meis S, Pape HC. Postsynaptic mechanisms underlying responsiveness of amygdaloid neurons to nociceptin/orphanin FQ. J Neurosci. 1998;18:8133–44.

    PubMed  PubMed Central  CAS  Google Scholar 

Download references


We wish thank Linda M. Rorick-Kehn for the scientific inputs and thoughtful comments on the work. We also thank Rina Righi, Agostino Marchi, Mariangela Fiorelli for animal care as well as Alfredo Fiorelli for his excellent technical support. Authors gratefully thank Federica Benvenuti, Marina Antonini, Martina Mondaini, and Maria Sole Centanni for their support in behaviorally testing the animals. This work was supported by the National Institutes of Health, grant RO1 AA014351 (to FW and RC) from the National Institute on Alcohol Abuse and Alcoholism.

Author information




AMB and RC were responsible for the study concept and design. AMB performed surgeries, behavioral testing, data analysis and wrote the paper. YF performed surgeries and behavioral tests. SS, AD, and SDC performed behavioral tests. MP, MU, FW, and RC provided critical revision of the paper for important intellectual content. RC and MP contributed to write the paper. All authors critically reviewed the content and approved the final version for publication.

Corresponding author

Correspondence to Roberto Ciccocioppo.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Borruto, A.M., Fotio, Y., Stopponi, S. et al. NOP receptor antagonism attenuates reinstatement of alcohol-seeking through modulation of the mesolimbic circuitry in male and female alcohol-preferring rats. Neuropsychopharmacol. 46, 2121–2131 (2021).

Download citation


Quick links