Psychopharmacology

, Volume 189, Issue 2, pp 175–186 | Cite as

Dissociation between opioid and CRF1 antagonist sensitive drinking in Sardinian alcohol-preferring rats

  • Valentina Sabino
  • Pietro Cottone
  • George F. Koob
  • Luca Steardo
  • Mei J. Lee
  • Kenner C. Rice
  • Eric P. Zorrilla
Original Investigation

Abstract

Rationale

The role of positive vs negative ethanol reinforcement in ethanol intake of Sardinian alcohol-preferring (sP) rats is unclear.

Objectives

To test the hypothesis that spontaneous ethanol self-administration of sP rats was sensitive to the opioid receptor antagonist naltrexone, whereas withdrawal-induced, but not spontaneous, ethanol self-administration would be sensitive to corticotropin-releasing factor1 (CRF1) antagonists, implicating differential roles for positive and negative reinforcement, respectively.

Methods

Male sP rats operantly (FR1, 30 min/day) self-administered ethanol (10% v/v) until responding stabilized. One group (n=11) was made ethanol dependent through intermittent ethanol vapor exposure. Both nondependent (n = 10) and dependent rats received the CRF1 antagonist LWH-63 (5, 10, and 20 mg/kg, s.c.). Separate nondependent sP rats (n = 10) received the opioid antagonist naltrexone (16, 50, 150, and 450 μg/kg, s.c.). Finally, CRF1 antagonists (MJL-1-109-2, LWH-63, and R121919) were studied for their actions on home-cage ethanol drinking in nondependent sP rats (n = 6–8/group) under continuous, limited-access, or stressed conditions.

Results

Naltrexone potently reduced ethanol self-administration in nondependent sP rats. LWH-63 reduced heightened ethanol self-administration of vapor-sensitive, dependent sP rats. CRF1 antagonists did not reduce ethanol intake in nondependent sP rats. R121919 (10 mg/kg, s.c.) retained antistress activity in sP rats, blunting novelty stress-induced suppression of ethanol intake.

Conclusions

Spontaneous ethanol self-administration of sP rats was opioid dependent with CRF1 receptors implicated in withdrawal-induced drinking. Opioid and CRF1 receptors play different roles in ethanol reinforcement and perhaps the ethanol addiction cycle. Such distinctions may apply to subtypes of alcoholic patients who differ in their motivation to drink and ultimately treatment response.

Keywords

Sardinian alcohol-preferring or sP rat Ethanol or alcohol intake Genetic or selectively bred animal model Anxiety or stress Corticotropin-releasing factor or Corticotropin-releasing hormone or CRF or CRH CRF1 receptor antagonist or CRH1 receptor antagonist Opioids Naltrexone Withdrawal or abstinence Dependence 

Notes

Acknowledgments

This is manuscript number 18046 from The Scripps Research Institute. The authors gratefully recognize the technical assistance of Molly Brennan, Maury Cole, Robert Lintz, and Maegan Mattock and the editorial assistance of Mike Arends.

References

  1. American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders, IV-TR Edition. American Psychiatric Press, Washington DCGoogle Scholar
  2. Balakleevsky A, Colombo G, Fadda F, Gessa GL (1990) Ro 19-4603, a benzodiazepine receptor inverse agonist, attenuates voluntary ethanol consumption in rats selectively bred for high ethanol preference. Alcohol Alcohol 25:449–452PubMedGoogle Scholar
  3. Baldwin HA, Rassnick S, Rivier J, Koob GF, Britton KT (1991) CRF antagonist reverses the “anxiogenic” response to ethanol withdrawal in the rat. Psychopharmacology 103:227–232PubMedCrossRefGoogle Scholar
  4. Bienkowski P, Kostowski W, Koros E (1999) Ethanol-reinforced behaviour in the rat: effects of naltrexone. Eur J Pharmacol 374:321–327PubMedCrossRefGoogle Scholar
  5. Cappell H, Herman CP (1972) Alcohol and tension reduction. A review. Q J Stud Alcohol 33:33–64PubMedGoogle Scholar
  6. Carrera MR, Schulteis G, Koob GF (1999) Heroin self-administration in dependent Wistar rats: increased sensitivity to naloxone. Psychopharmacology 144:111–120PubMedCrossRefGoogle Scholar
  7. Chen C, Wilcoxen KM, Huang CQ, Xie YF, McCarthy JR, Webb TR, Zhu YF, Saunders J, Liu XJ, Chen TK, Bozigian H, Grigoriadis DE (2004) Design of 2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylaminopyrazolo[1,5-a]pyrimidine (NBI 30775/R121919) and structure-activity relationships of a series of potent and orally active corticotropin-releasing factor receptor antagonists. J Med Chem 47:4787–4798PubMedCrossRefGoogle Scholar
  8. Colombo G (1997) ESBRA-Nordmann 1996 Award Lecture: ethanol drinking behaviour in Sardinian alcohol-preferring rats. Alcohol Alcohol 32:443–453PubMedGoogle Scholar
  9. Colombo G, Agabio R, Lobina C, Reali R, Zocchi A, Fadda F, Gessa GL (1995) Sardinian alcohol-preferring rats: a genetic animal model of anxiety. Physiol Behav 57:1181–1185PubMedCrossRefGoogle Scholar
  10. Colombo G, Agabio R, Lobina C, Reali R, Vacca G, Gessa GL (1998) Stimulation of locomotor activity by voluntarily consumed ethanol in Sardinian alcohol-preferring rats. Eur J Pharmacol 357:109–113PubMedCrossRefGoogle Scholar
  11. Conger JJ (1956) Alcoholism: theory, problem and challenge. II. Reinforcement theory and the dynamics of alcoholism. Q J Stud Alcohol 17:296–305PubMedGoogle Scholar
  12. Delamater AR, Sclafani A, Bodnar RJ (2000) Pharmacology of sucrose-reinforced place-preference conditioning: effects of naltrexone. Pharmacol Biochem Behav 65:697–704PubMedCrossRefGoogle Scholar
  13. Dundon W, Lynch KG, Pettinati HM, Lipkin C (2004) Treatment outcomes in type A and B alcohol dependence 6 months after serotonergic pharmacotherapy. Alcohol Clin Exp Res 28:1065–1073PubMedCrossRefGoogle Scholar
  14. Funk CK, Zorrilla EP, Lee JM, Rice KC, Koob GF (2006) CRF1 Antagonists selectively reduce ethanol self-administration in ethanol-dependent rats. Biol Psychiatry (in press)Google Scholar
  15. Gutman DA, Owens MJ, Skelton KH, Thrivikraman KV, Nemeroff CB (2003) The corticotropin-releasing factor1 receptor antagonist R121919 attenuates the behavioral and endocrine responses to stress. J Pharmacol Exp Ther 304:874–880PubMedCrossRefGoogle Scholar
  16. He L, Gilligan PJ, Zaczek R, Fitzgerald LW, McElroy J, Shen HS, Saye JA, Kalin NH, Shelton S, Christ D, Trainor G, Hartig P (2000) 4-(1,3-Dimethoxyprop-2-ylamino)-2,7-dimethyl-8-(2, 4-dichlorophenyl)pyrazolo[1,5-a]-1,3,5-triazine: a potent, orally bioavailable CRF(1) receptor antagonist. J Med Chem 43:449–456PubMedCrossRefGoogle Scholar
  17. Heinrichs SC, De Souza EB, Schulteis G, Lapsansky JL, Grigoriadis DE (2002) Brain penetrance, receptor occupancy and antistress in vivo efficacy of a small molecule corticotropin releasing factor type I receptor selective antagonist. Neuropsychopharmacology 27:194–202CrossRefGoogle Scholar
  18. Hope PJ, Turnbull H, Farr S, Morley JE, Rice KC, Chrousos GP, Torpy DJ, Wittert GA (2000) Peripheral administration of CRF and urocortin: effects on food intake and the HPA axis in the marsupial Sminthopsis crassicaudata. Peptides 21:669–677PubMedCrossRefGoogle Scholar
  19. Hsin LW, Tian X, Webster EL, Coop A, Caldwell TM, Jacobson AE, Chrousos GP, Gold PW, Habib KE, Ayala A, Eckelman WC, Contoreggi C, Rice KC (2002) CRHR1 receptor binding and lipophilicity of pyrrolopyrimidines, potential nonpeptide corticotropin-releasing hormone type 1 receptor antagonists. Bioorg Med Chem 10:175–183PubMedCrossRefGoogle Scholar
  20. Jagoda E, Contoreggi C, Lee MJ, Kao CH, Szajek LP, Listwak S, Gold P, Chrousos G, Greiner E, Kim BM, Jacobson AE, Rice KC, Eckelman W (2003) Autoradiographic visualization of corticotropin releasing hormone type 1 receptors with a nonpeptide ligand: synthesis of [(76)Br]MJL-1-109-2. J Med Chem 46:3559–3562PubMedCrossRefGoogle Scholar
  21. Koob GF, Roberts AJ, Kieffer BL, Heyser CJ, Katner SN, Ciccocioppo R, Weiss F (2003) Animal models of motivation for drinking in rodents with a focus on opioid receptor neuropharmacology. Recent Dev Alcohol 16:263–281PubMedGoogle Scholar
  22. Koob GF (2003) Alcoholism: allostasis and beyond. Alcohol Clin Exp Res 27:232–243PubMedGoogle Scholar
  23. Kunzel HE, Zobel AW, Nickel T, Ackl N, Uhr M, Sonntag A, Ising M, Holsboer F (2003) Treatment of depression with the CRH-1-receptor antagonist R121919: endocrine changes and side effects. J Psychiatr Res 37:525–533PubMedCrossRefGoogle Scholar
  24. Lesch OM, Walter H (1996) Subtypes of alcoholism and their role in therapy. Alcohol Alcohol Suppl 1:63–67PubMedGoogle Scholar
  25. Levine AS, Billington CJ (2004) Opioids as agents of reward-related feeding: a consideration of the evidence. Physiol Behav 82:57–61PubMedCrossRefGoogle Scholar
  26. Litt MD, Babor TF, DelBoca FK, Kadden RM, Cooney NL (1992) Types of alcoholics, II. Application of an empirically derived typology to treatment matching. Arch Gen Psychiatry 49:609–614PubMedGoogle Scholar
  27. Liu X, Weiss F (2002) Additive effect of stress and drug cues on reinstatement of ethanol seeking: exacerbation by history of dependence and role of concurrent activation of corticotropin-releasing factor and opioid mechanisms. J Neurosci 22:7856–7861PubMedGoogle Scholar
  28. Martin TJ, Kim SA, Lyupina Y, Smith JE (2002) Differential involvement of mu-opioid receptors in the rostral versus caudal nucleus accumbens in the reinforcing effects of heroin in rats: evidence from focal injections of beta-funaltrexamine. Psychopharmacology (Berl) 161:152–159CrossRefGoogle Scholar
  29. Mason BJ (2003) Acamprosate and naltrexone treatment for alcohol dependence: an evidence-based risk-benefits assessment. Eur Neuropsychopharmacol 13:469–475PubMedCrossRefGoogle Scholar
  30. Mason BJ, Salvato FR, Williams LD, Ritvo EC, Cutler RB (1999) A double-blind, placebo-controlled study of oral nalmefene for alcohol dependence. Arch Gen Psychiatry 56:719–724PubMedCrossRefGoogle Scholar
  31. McBride WJ, Li TK (1998) Animal models of alcoholism: neurobiology of high alcohol-drinking behavior in rodents. Crit Rev Neurobiol 12:339–369PubMedGoogle Scholar
  32. Merikangas KR, Stevens DE, Fenton B, Stolar M, O’Malley S, Woods SW, Risch N (1998) Co-morbidity and familial aggregation of alcoholism and anxiety disorders. Psychol Med 28:773–788PubMedCrossRefGoogle Scholar
  33. Merlo-Pich E, Lorang M, Yeganeh M, Rodriguez de FF, Raber J, Koob GF, Weiss F (1995) Increase of extracellular corticotropin-releasing factor-like immunoreactivity levels in the amygdala of awake rats during restraint stress and ethanol withdrawal as measured by microdialysis. J Neurosci 15:5439–5447PubMedGoogle Scholar
  34. O’Dell LE, Roberts AJ, Smith RT, Koob GF (2004) Enhanced alcohol self-administration after intermittent versus continuous alcohol vapor exposure. Alcohol Clin Exp Res 28:1676–1682PubMedGoogle Scholar
  35. Ohata H, Arai K, Shibasaki T (2002) Effect of chronic administration of a CRF1 receptor antagonist, CRA1000, on locomotor activity and endocrine responses to stress. Eur J Pharmacol 457:201–206PubMedCrossRefGoogle Scholar
  36. Olmstead MC, Burns LH (2005) Ultra-low-dose naltrexone suppresses rewarding effects of opiates and aversive effects of opiate withdrawal in rats. Psychopharmacology (Berl) 181:576–581CrossRefGoogle Scholar
  37. Overstreet DH, Knapp DJ, Breese GR (2004) Modulation of multiple ethanol withdrawal-induced anxiety-like behavior by CRF and CRF1 receptors. Pharmacol Biochem Behav 77:405–413PubMedCrossRefGoogle Scholar
  38. Perfumi M, Santoni M, Ciccocioppo R, Massi M (2002) Blockade of gamma-aminobutyric acid receptors does not modify the inhibiton of ethanol intake induced by Hypericum perforatum in rats. Alcohol Alcohol 37:540–546PubMedGoogle Scholar
  39. Pettinati HM, Volpicelli JR, Kranzler HR, Luck G, Rukstalis MR, Cnaan A (2000) Sertraline treatment for alcohol dependence: interactive effects of medication and alcoholic subtype. Alcohol Clin Exp Res 24:1041–1049PubMedCrossRefGoogle Scholar
  40. Rassnick S, Heinrichs SC, Britton KT, Koob GF (1993) Microinjection of a corticotropin-releasing factor antagonist into the central nucleus of the amygdala reverses anxiogenic-like effects of ethanol withdrawal. Brain Res 605:25–32PubMedCrossRefGoogle Scholar
  41. Richter RM, Zorrilla EP, Basso AM, Koob GF, Weiss F (2000) Altered amygdalar CRF release and increased anxiety-like behavior in Sardinian alcohol-preferring rats: a microdialysis and behavioral study. Alcohol Clin Exp Res 24:1765–1772PubMedCrossRefGoogle Scholar
  42. Roberts AJ, Heyser CJ, Cole M, Griffin P, Koob GF (2000) Excessive ethanol drinking following a history of dependence: animal model of allostasis. Neuropsychopharmacology 22:581–594PubMedCrossRefGoogle Scholar
  43. Rogers J, Wiener SG, Bloom FE (1979) Long-term ethanol administration methods for rats: advantages of inhalation over intubation or liquid diets. Behav Neural Biol 27:466–486PubMedCrossRefGoogle Scholar
  44. Samson HH (1986) Initiation of ethanol reinforcement using a sucrose-substitution procedure in food- and water-sated rats. Alcohol Clin Exp Res 10:436–442PubMedGoogle Scholar
  45. Sarnyai Z, Shaham Y, Heinrichs SC (2001) The role of corticotropin-releasing factor in drug addiction. Pharmacol Rev 53:209–243PubMedGoogle Scholar
  46. Timpl P, Spanagel R, Sillaber I, Kresse A, Reul JM, Stalla GK, Blanquet V, Steckler T, Holsboer F, Wurst W (1998) Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1. Nat Genet 19:162–166PubMedCrossRefGoogle Scholar
  47. Vacca G, Serra S, Brunetti G, Carai MA, Samson HH, Gessa GL, Colombo G (2002) Operant self-administration of ethanol in Sardinian alcohol-preferring rats. Alcohol Clin Exp Res 26:1678–1685PubMedCrossRefGoogle Scholar
  48. Valdez GR, Koob GF (2004) Allostasis and dysregulation of corticotropin-releasing factor and neuropeptide Y systems: implications for the development of alcoholism. Pharmacol Biochem Behav 79:671–689PubMedCrossRefGoogle Scholar
  49. Valdez GR, Roberts AJ, Chan K, Davis H, Brennan M, Zorrilla EP, Koob GF (2002) Increased ethanol self-administration and anxiety-like behavior during acute ethanol withdrawal and protracted abstinence: regulation by corticotropin-releasing factor. Alcohol Clin Exp Res 26:1494–1501PubMedCrossRefGoogle Scholar
  50. Walker JR, Ahmed SH, Gracy KN, Koob GF (2000) Microinjections of an opiate receptor antagonist into the bed nucleus of the stria terminalis suppress heroin self-administration in dependent rats. Brain Res 854:85–92PubMedCrossRefGoogle Scholar
  51. Zobel AW, Nickel T, Kunzel HE, Ackl N, Sonntag A, Ising M, Holsboer F (2000) Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated. J Psychiatr Res 34:171–181PubMedCrossRefGoogle Scholar
  52. Zorrilla EP, Koob GF (2004) The therapeutic potential of CRF1 antagonists for anxiety. Expert Opin Investig Drugs 13:799–828PubMedCrossRefGoogle Scholar
  53. Zorrilla EP, Valdez GR, Nozulak J, Koob GF, Markou A (2002) Effects of antalarmin, a CRF type 1 receptor antagonist, on anxiety-like behavior and motor activation in the rat. Brain Res 952:188–199PubMedCrossRefGoogle Scholar
  54. Zorrilla EP, Fekete EM, Mason BJ, Wirsching P, Janda KD, Koob GF (2003) CRF1 receptor antagonists for anxiety. Eur Neuropsychopharmacol 13:s130–s131CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Valentina Sabino
    • 1
    • 4
  • Pietro Cottone
    • 1
    • 2
    • 4
  • George F. Koob
    • 1
  • Luca Steardo
    • 2
  • Mei J. Lee
    • 3
  • Kenner C. Rice
    • 3
  • Eric P. Zorrilla
    • 1
    • 4
  1. 1.Molecular and Integrative Neurosciences DepartmentSP30-2400, The Scripps Research InstituteLa JollaUSA
  2. 2.Department of Human Physiology and PharmacologyUniversity of Rome La SapienzaRomeItaly
  3. 3.Laboratory of Medicinal ChemistryNational Institute of Diabetes and Digestive and Kidney DiseasesBethesdaUSA
  4. 4.Harold L. Dorris Neurological Research InstituteThe Scripps Research InstituteLa JollaUSA

Personalised recommendations