Skip to main content
Log in

Attenuation of ethanol self-administration and of conditioned reinstatement of alcohol-seeking behaviour by the antiopioid peptide nociceptin/orphanin FQ in alcohol-preferring rats

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the opioid-like orphan receptor NOP, was shown to reduce home-cage ethanol consumption, ethanol-induced conditioned place preference and stress-induced reinstatement of alcohol-seeking behaviour.

Objectives

The present study, using genetically selected Marchigian Sardinian alcohol-preferring (msP) rats, was designed to evaluate the effect of this opioid peptide on 10% ethanol and 10% sucrose self-administration, under a fixed-ratio 1 (FR 1) or a progressive-ratio (PR) schedule of reinforcement. Furthermore, using an experimental model of relapse in which rats were trained to lever press for ethanol in the presence of the discriminative stimulus of an orange odour (S+) and a 1-s cue light (CS+) or for water in the presence of anise odour (S) and 1-s white noise (CS), the effect of N/oFQ on cue-induced reinstatement of extinguished ethanol responding was investigated.

Results

Sub-chronic (6 days) intracerebroventricular (i.c.v.) injection of 0.5 μg or 1.0 μg N/OFQ per rat significantly reduced alcohol self-administration under both the FR 1 and PR schedules of reinforcement. Conversely, i.c.v. administration of 0.5, 1.0 or 4.0 μg of the peptide per rat did not affect sucrose self-administration. In addition, i.c.v. N/OFQ (1.0–2.0 μg per rat) significantly inhibited the reinstatement of extinguished ethanol responding under an S+/CS+ condition, whereas lever pressing under S/CS was not altered.

Conclusions

The present study demonstrates that the reinforcing effects of ethanol are markedly blunted by activation of the opioidergic N/OFQ receptor system. Moreover, the data provide evidence of the efficacy of N/OFQ to prevent reinstatement of ethanol-seeking behaviour elicited by environmental conditioned stimuli.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, Washington, DC

  • Ciccocioppo R, Panocka I, Polidori C, Regoli D, Massi M (1999) Effect of nociceptin on alcohol intake in alcohol-preferring rats. Psychopharmacology 141:220–224

    Article  CAS  PubMed  Google Scholar 

  • Ciccocioppo R, Angeletti S, Sanna PP, Weiss F, Massi M (2000) Effect of nociceptin/orphanin FQ on the rewarding properties of morphine. Eur J Pharmacol 404:153–159

    CAS  PubMed  Google Scholar 

  • Ciccocioppo R, Angeletti S, Weiss F (2001a) Long-lasting resistance to extinction of response reinstatement induced by ethanol-related stimuli: role of genetic ethanol preference. Alcohol Clin Exp Res 25:1414–1419

    Google Scholar 

  • Ciccocioppo R, Martin-Fardon R, Weiss F, Massi M (2001b) Nociceptin/orphanin FQ inhibits stress- and CRF-induced anorexia in rats. Neuroreport 12:1145–1149

    CAS  PubMed  Google Scholar 

  • Ciccocioppo R, Martin-Fardon R, Weiss F (2002a) Effect of selective blockade of mu(1) or delta opioid receptors on reinstatement of alcohol-seeking behavior by drug-associated stimuli in rats. Neuropsychopharmacology 27:391–399

    Google Scholar 

  • Ciccocioppo R, Polidori C, Antonelli L, Salvadori S, Guerrini R, Massi M (2002b) Pharmacological characterization of the nociceptin receptor which mediates reduction of alcohol drinking in rats. Peptides 23:117–125

    Article  CAS  PubMed  Google Scholar 

  • Ciccocioppo R, Biondini M, Antonelli L, Wichmann J, Jenck F, Massi M (2002c) Reversal of stress- and CRF-induced anorexia in rats by the synthetic nociceptin/orphanin FQ receptor agonist, Ro 64–6198. Psychopharmacology 161:113–119

    Article  CAS  PubMed  Google Scholar 

  • Darland T, Heinricher MM, Grandy DK (1998) Orphanin FQ/nociceptin: a role in pain and analgesia, but so much more. Trends Neurosci 21:215–221

    CAS  PubMed  Google Scholar 

  • Devine DP, Leone P, Carlezon WA Jr, Wise RA (1993a) Ventral mesencephalic delta opioid receptors are involved in modulation of basal mesolimbic dopamine neurotransmission: an anatomical localization study. Brain Res 622:348–352

    CAS  PubMed  Google Scholar 

  • Devine DP, Leone P, Wise RA (1993b) Mesolimbic dopamine neurotransmission is increased by administration of mu-opioid receptor antagonists. Eur J Pharmacol 243:55–64

    Article  CAS  PubMed  Google Scholar 

  • Devine DP, Reinscheid RK, Monsma FJ Jr, Civelli O, Akil H (1996) The novel neuropeptide orphanin FQ fails to produce conditioned place preference or aversion. Brain Res 727:225–229

    CAS  PubMed  Google Scholar 

  • Di Chiara G, North RA (1992) Neurobiology of opiate abuse. Trends Pharmacol Sci 13:185–193

    PubMed  Google Scholar 

  • Di Giannuario A, Pieretti S (2000) Nociceptin differentially affects morphine-induced dopamine release from the nucleus accumbens and nucleus caudate in rats. Peptides 21:1125–1130

    PubMed  Google Scholar 

  • Di Giannuario A, Pieretti S, Catalani A, Loizzo A (1999) Orphanin FQ reduces morphine-induced dopamine release in the nucleus accumbens: a microdialysis in rats. Neurosci Lett 272:183–186

    PubMed  Google Scholar 

  • Everitt BJ, Wolf ME (2002) Psychomotor stimulant addiction: a neural systems perspective. J Neurosci 22:3312–3320

    CAS  PubMed  Google Scholar 

  • Fadda F, Mosca E, Colombo G, Gessa GL (1990) Alcohol-preferring rats: genetic sensitivity to alcohol-induced stimulation of dopamine metabolism. Physiol Behav 47:727–729

    Article  CAS  PubMed  Google Scholar 

  • Gessa GL, Colombo G, Fadda F (1991) Rat lines genetically selected for difference in voluntary ethanol consumption. In: Meltzer HY, Nerozzi D (eds) Current practices and future developments in the pharmacotherapy of mental disorders. Excerpta Medica, Amsterdam, pp 193–200

  • Gonzales RA, Weiss F (1998) Suppression of ethanol-reinforced behavior by naltrexone is associated with attenuation of the ethanol-induced increase in dialysate dopamine levels in the nucleus accumbens. J Neurosci 18:10663–10671

    CAS  PubMed  Google Scholar 

  • Henderson G, McKnight AT (1997) The orphan opioid receptor and its endogenous ligand—nociceptin/orphanin FQ. Trends Pharmacol Sci 18:293–300

    CAS  PubMed  Google Scholar 

  • Herz A (1997) Endogenous opioid systems and alcohol addiction. Psychopharmacology 129:99–111

    CAS  PubMed  Google Scholar 

  • Jenck F, Moreau JL, Martin JR, Kilpatrick GJ, Reinscheid RK, Monsma FJ Jr, Nothacker HP, Civelli O (1999) Orphanin FQ acts as an anxiolytic to attenuate behavioral responses to stress. Proc Natl Acad Sci U S A 94:14854–14858

    Article  Google Scholar 

  • Jenck F, Wichmann J, Dautzenberg FM, Moreau JL, Quagazzal AM, Martin JR, Lundstrom K, Cesura AM, Poli SM, Roever S, Kolczewski S, Sabine AG, Kilpatric G (2000) A synthetic agonist at the orphanin FQ/nociceptin receptor ORL1: anxiolytic profile in the rat. Proc Natl Acad Sci U S A 97:4938–4943

    Article  CAS  PubMed  Google Scholar 

  • Johnson SW, North RA (1992) Opioids excite dopamine neurons by hyperpolarization of local interneurons. J Neurosci 12:483–488

    PubMed  Google Scholar 

  • Katner SN, Kerr TM, Weiss F (1996) Ethanol anticipation enhances dopamine efflux in the nucleus accumbens of alcohol preferring (P) but not Wistar rats. Behav Pharmacol 7:669–674

    CAS  PubMed  Google Scholar 

  • Katner SN, Magalong JG, Weiss F (1999) Reinstatement of alcohol-seeking behavior by drug-associated discriminative stimuli after prolonged extinction in the rat. Neuropsychopharmacology 20:471–479

    Google Scholar 

  • King M, Chang A, Pasternak GW (1998) Functional blockade of opioid analgesia by orphanin FQ/nociceptin. Biochem Pharmacol 55:1537–1540

    Article  CAS  PubMed  Google Scholar 

  • Koob GF, Sanna PP, Bloom FE (1998) Neuroscience of addiction. Neuron 21:467–476

    CAS  PubMed  Google Scholar 

  • Kosten TR, Kleber HD (1984) Strategies to improve compliance with narcotic antagonists. Am J Drug Alcohol Abuse 10:249–266

    CAS  PubMed  Google Scholar 

  • Kotlinska J, Wichmann J, Legowska A, Rolka K, Silberring J (2002) Orphanin FQ/nociceptin but not Ro 65–6570 inhibits the expression of cocaine-induced conditioned place preference. Behav Pharmacol 13:229–235

    CAS  PubMed  Google Scholar 

  • Le AD, Poulos CX, Harding S, Watchus J, Juzytsch W, Shaham Y (1999) Effects of naltrexone and fluoxetine on alcohol self-administration and reinstatement of alcohol seeking induced by priming injections of alcohol and exposure to stress. Neuropsychopharmacology 21:435–444

    Google Scholar 

  • Lee C, Rodgers RJ (1990) Antinociceptive effects of elevated plus-maze exposure: influence of opiate receptor manipulations. Psychopharmacology 102:507–513

    CAS  PubMed  Google Scholar 

  • Liu X, Weiss F (2002) Reversal of ethanol-seeking behavior by D1 and D2 antagonists in an animal model of relapse: differences in antagonist potency in previously ethanol-dependent versus nondependent rats. J Pharmacol Exp Ther 300:882–889

    Google Scholar 

  • Maidment NT, Chen Y, Tan AM, Murphy NP, Leslie FM (2002) Rat ventral midbrain dopamine neurons express the orphanin FQ/nociceptin receptor ORL-1. Neuroreport 13:1137–1140

    CAS  PubMed  Google Scholar 

  • Martin-Fardon R, Ciccocioppo R, Massi M, Weiss F (2000) Nociceptin prevents stress-induced ethanol- but not cocaine-seeking behavior in rats. Neuroreport 11:1939–1943

    CAS  PubMed  Google Scholar 

  • McCusker CG, Brown K (1990) Alcohol-predictive cues enhance tolerance to and precipitate “craving” for alcohol in social drinkers. J Stud Alcohol 51:494–499

    CAS  PubMed  Google Scholar 

  • McCusker CG, Brown K (1991) The cue-responsivity phenomenon in dependent drinkers: ‘personality’ vulnerability and anxiety as intervening variables. Br J Addict 86:905–912

    CAS  PubMed  Google Scholar 

  • Meunier JC, Mollereau C, Toll L, Suaudeau C, Moisand C, Alvinerie P, Butour JL, Guillemot JC, Ferrara P, Monsarrat B, Mazarguil H, Vassart G, Parmentieer M, Costentin J (1995) Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor. Nature 377:532–535

    CAS  PubMed  Google Scholar 

  • Mogil JS, Pasternak GW (2001) The molecular and behavioral pharmacology of the orphanin FQ/nociceptin peptide and receptor family. Pharmacol Rev 53:381–415

    CAS  PubMed  Google Scholar 

  • Mogil JS, Grisel JE, Reinscheid RK, Civelli O, Belknap JK, Grandy DK (1996) Orphanin FQ is a functional anti-opioid peptide. Neuroscience 75:333–337

    Article  CAS  PubMed  Google Scholar 

  • Monti PM, Rohsenow DJ, Rubonis AV, Niaura RS, Sirota AD, Colby SM, Abrams DB (1993) Alcohol cue reactivity: effects of detoxification and extended exposure. J Stud Alcohol 54:235–245

    CAS  PubMed  Google Scholar 

  • Monti PM, Rohsenow DJ, Hutchison KE, Swift RM, Mueller TI, Colby SM, Brown RA, Gulliver SB, Gordon A, Abrams DB (1999) Naltrexone’s effect on cue-elicited craving among alcoholics in treatment. Alcohol Clin Exp Res 23:1386–1394

    CAS  PubMed  Google Scholar 

  • Mollereau C, Mouledous L (2000) Tissue distribution of the opioid receptor-like (ORL1) receptor. Peptides 21:907–917

    Article  CAS  PubMed  Google Scholar 

  • Murphy NP, Maidment NT (1999) Orphanin FQ/nociceptin modulation of mesolimbic dopamine transmission determined by microdialysis. J Neurochem 73:179–186

    CAS  PubMed  Google Scholar 

  • Murphy NP, Ly HT, Maidment NT (1996) Intracerebroventricular orphanin FQ/nociceptin suppresses dopamine release in the nucleus accumbens of anaesthetized rats. Neuroscience 75:1–4

    CAS  PubMed  Google Scholar 

  • Murphy NP, Lee Y, Maidment NT (1999) Orphanin FQ/nociceptin blocks acquisition of morphine place preference. Brain Res 832:168–170

    CAS  PubMed  Google Scholar 

  • Norton CS, Neal CR, Kumar S, Akil H, Watson SJ (2002) Nociceptin/orphanin FQ and opioid receptor-like receptor mRNA expression in dopamine systems. J Comp Neurol 444:358–368

    Google Scholar 

  • O’Brien CP, McLellan AT (1996) Myths about the treatment of addiction. Lancet 347:237–240

    CAS  PubMed  Google Scholar 

  • O’Brien CP, Childress AR, McLellan AT, Ehrman R (1990) Integrating systematic cue exposure with standard treatment in recovering drug dependent patients. Addict Behav 15:355–365

    CAS  PubMed  Google Scholar 

  • O’Brien CP, Childress AR, Ehrman R, Robbins SJ (1998) Conditioning factors in drug abuse: can they explain compulsion? J Psychopharmacol 12:15–22

    CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, 2nd edn. Academic Press, North Ryde, Australia

  • Rabinowitz J, Cohen H, Tarrasch R, Kotler M (1997) Compliance to naltrexone treatment after ultra-rapid opiate detoxification: an open label naturalistic study. Drug Alcohol Depend 47:77–86

    Article  CAS  PubMed  Google Scholar 

  • Rabinowitz J, Cohen H, Atias S (2002) Outcomes of naltrexone maintenance following ultra-rapid opiate detoxification versus intensive inpatient detoxification. Am J Addict 11:52–56

    Article  PubMed  Google Scholar 

  • Reinscheid RK, Nothacker HP, Bourson A, Ardati A, Henningsen RA, Bunzow JR, Grandy DK, Langen H, Monsma FJ Jr, Civelli O (1995) Orphanin FQ: neuropeptide that activates an opioid-like G protein-coupled receptor. Science 270:792–794

    CAS  PubMed  Google Scholar 

  • Reinscheid RK, Higelin J, Henningsen RA, Monsma FJ Jr, Civelli O (1998) Structures that delineate orphanin FQ and dynorphin-A pharmacological selectivities. J Biol Chem 273:1490–1495

    CAS  PubMed  Google Scholar 

  • Samson HS (1986) Initiation of ethanol reinforcement using a sucrose-substitution procedure in food- and water-sated rats. Alcohol Clin Exp Res 10:436–442

    CAS  PubMed  Google Scholar 

  • Staiger PK, White JM (1991) Cue reactivity on alcohol abusers: stimulus specificity and extinction of the response. Addict Behav 16:211–221

    CAS  PubMed  Google Scholar 

  • Wagner EJ, Ronnekleiv OK, Grandy DK, Kelly MJ (1998) The peptide orphanin FQ inhibits beta-endorphin neurons and neurosecretory cells in the hypothalamic arcuate nucleus by activating an inwardly-rectifying K+ conductance. Neuroendocrinology 67:73–82

    CAS  PubMed  Google Scholar 

  • Weiss F, Lorang MT, Bloom FE, Koob GF (1993) Oral alcohol self-administration stimulates dopamine release in the rat nucleus accumbens: genetic and motivational determinants. J Pharmacol Exp Ther 267:250–258

    Google Scholar 

  • Weiss F, Ciccocioppo R, Parsons LH, Katner S, Liu X, Zorrilla EP, Valdez GR, Ben-Shahar O, Angeletti S, Richter RR (2001) Compulsive drug-seeking behavior and relapse. Neuroadaptation, stress, and conditioning factors. Ann N Y Acad Sci 937:1–26

    CAS  PubMed  Google Scholar 

  • Wise RA (1998) Drug activation of brain reward pathways. Drug Alcohol Depend 51:13–22

    CAS  PubMed  Google Scholar 

  • Zheng F, Grandy DK, Johnson SW (2002) Actions of orphanin FQ/nociceptin on rat ventral tegmental area neurons in vitro. Br J Pharmacol 136:1065–1071

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Mike Arends for his assistance with manuscript preparation and Marino Cucculelli for technical assistance and animal care. The study was supported by the EU 5th Framework Programme, grant QLRT-2001–01048 (to RC), the NIH/NIAAA grant AA 10531 (to FW) and by grant MIUR 2002 to (MM).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Roberto Ciccocioppo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ciccocioppo, R., Economidou, D., Fedeli, A. 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. Psychopharmacology 172, 170–178 (2004). https://doi.org/10.1007/s00213-003-1645-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-003-1645-1

Keywords

Navigation