, Volume 196, Issue 3, pp 473–482 | Cite as

CRF1 receptor antagonists attenuate escalated cocaine self-administration in rats

  • Sheila E. Specio
  • Sunmee WeeEmail author
  • Laura E. O’Dell
  • Benjamin Boutrel
  • Eric P. Zorrilla
  • George F. Koob
Original Investigation



Previous work suggests a role for stress-related corticotropin-releasing factor (CRF) systems in cocaine dependence. However, the involvement of activation of CRF1 receptors in rats self-administering cocaine with extended access is unknown.


The current study examined whether CRF1 receptor antagonist administration alters cocaine self-administration in animals given extended access.

Materials and methods

Wistar rats (n = 32) acquired cocaine self-administration (0.66 mg/kg per infusion) in 1 h sessions for up to 11 days. Rats then were assigned to receive either daily short (1 h, ShA) or long (6 h, LgA) access to cocaine self-administration (n = 7–9 per group). Following escalation of intake, animals received one of two selective CRF1 antagonists: antalarmin (6.3–25 mg/kg, i.p.) or N,N-bis(2-methoxyethyl)-3-(4-methoxy-2-methylphenyl)-2,5-dimethyl-pyrazolo[1,5a]pyrimidin-7-amine (MPZP; 3.6–27.5 mg/kg, s.c.).


By day 11 of the escalation period, LgA rats increased their cocaine intake, reaching an intake level of 15.1 mg/kg, compared to 11.1 mg/kg in ShA rats, during the first hour of sessions. Antalarmin reduced cocaine self-administration at the highest dose selectively in the LgA group but not the ShA group. MPZP reduced cocaine intake both in LgA and ShA rats. However, MPZP did so at a lower dose in LgA rats than in ShA rats. Within the LgA group, MPZP decreased cocaine intake in the first 10 min (loading phase) as well as in the latter session intake (maintenance phase).


The data suggest that hypersensitivity of the CRF system occurs with extended access to cocaine self-administration and that this altered CRF system may contribute to the increased motivation to self-administer cocaine that develops during psychostimulant dependence.


Cocaine Self-administration Escalation Rats Corticotropin-releasing factor Addiction Antalarmin MPZP 



We gratefully acknowledge the technical assistance of Yanabel Grant and Robert Lintz and the chemical expertise of Kim Janda and Pete Wirsching for MPZP synthesizing. Additionally, we thank Mike Arends for editorial assistance. This is publication number 18741 from The Scripps Research Institute. The experimental protocol was in compliance with the National Institutes of Health Guide for Care and Use of Laboratory Animals (The National Academies Press, 1996). Additionally, there is no relationship with the organization supporting this research and no conflict of interest.


  1. Ahmed SH, Kenny PJ, Koob GF, Markou A (2002) Neurobiological evidence for hedonic allostasis associated with escalating cocaine use. Nat Neurosci 5:625–626PubMedGoogle Scholar
  2. Ahmed SH, Koob GF (1998) Transition from moderate to excessive drug intake: change in hedonic set point. Science 282:298–300PubMedCrossRefGoogle Scholar
  3. American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Press, Washington DCGoogle Scholar
  4. Aujla H, Martin-Fardon R, Weiss F (2007) Rats with extended access to cocaine exhibit increased stress reactivity and sensitivity to the anxiolytic-like effects of the mGluR 2/3 agonist LY379268 during abstinence. Neuropsychopharmacology (in press)Google Scholar
  5. 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
  6. Bale TL, Vale WW (2004) CRF and CRF receptors: role in stress responsivity and other behaviors. Annu Rev Pharmacol Toxicol 44:525–557PubMedCrossRefGoogle Scholar
  7. Basso AM, Spina M, Rivier J, Vale W, Koob GF (1999) Corticotropin-releasing factor antagonist attenuates the “anxiogenic-like” effect in the defensive burying paradigm but not in the elevated plus-maze following chronic cocaine in rats. Psychopharmacology 145:21–30PubMedCrossRefGoogle Scholar
  8. Bewick V, Cheek L, Ball J (2004) Statistics review 9: One-way analysis of variance. Crit Care 8:130–136PubMedCrossRefGoogle Scholar
  9. Bretz F, Pinheiro JC, Branson M (2004) On a hybrid method in dose finding studies. Methods Inf Med 43:457–460PubMedGoogle Scholar
  10. Broadbear JH, Winger G, Woods JH (1999) Cocaine-reinforced responding in rhesus monkeys: pharmacological attenuation of the hypothalamic-pituitary-adrenal axis response. J Pharmacol Exp Ther 290:1347–1355PubMedGoogle Scholar
  11. Bruijnzeel AW, Zislis G, Wilson C, Gold MS (2007) Antagonism of CRF receptors prevents the deficit in brain reward function associated with precipitated nicotine withdrawal in rats. Neuropsychopharmacology 32:955–963PubMedCrossRefGoogle Scholar
  12. Caine SB, Lintz R, Koob GF (1993) Intravenous drug-self-administration techniques in animals. In: Sahgal A (ed) Behavioural Neuroscience: a practical approach, vol 2. Oxford University Press, New York, pp 117–143Google Scholar
  13. Chang CP, Pearse RV, O’Connell S, Rosenfeld MG (1993) Identification of a seven transmembrane helix receptor for corticotropin-releasing factor and sauvagine in mammalian brain. Neuron 11:1187–1195PubMedCrossRefGoogle Scholar
  14. Cummings S, Elde R, Ells J, Lindall A (1983) Corticotropin-releasing factor immunoreactivity is widely distributed within the central nervous system of the rat: an immunohistochemical study. J Neurosci 3:1355–1368PubMedGoogle Scholar
  15. De Souza EB (1995) Corticotropin-releasing factor receptors: physiology, pharmacology, biochemistry and role in central nervous system and immune disorders. Psychoneuroendocrinology 20:789–819PubMedCrossRefGoogle Scholar
  16. Erb S, Petrovic A, Yi D, Kayyali H (2006) Central injections of CRF reinstate cocaine seeking in rats after postinjection delays of up to 3 h: an influence of time and environmental context. Psychopharmacology 187:112–120PubMedCrossRefGoogle Scholar
  17. Erb S, Salmaso N, Rodaros D, Stewart J (2001) A role for the CRF-containing pathway from central nucleus of the amygdala to bed nucleus of the stria terminalis in the stress-induced reinstatement of cocaine seeking in rats. Psychopharmacology 158:360–365PubMedCrossRefGoogle Scholar
  18. Fekete EM, Zorrilla EP (2007) Physiology, pharmacology, and therapeutic relevance of urocortins in mammals: Ancient CRF paralogs. Front Neuroendocrinol 28:1–27PubMedCrossRefGoogle Scholar
  19. Fekete EM Zorrilla EP, Mason BJ, Wirsching P, Janda KD, Koob GF (2003) Anxiolytic-like effects of type 1 corticotropin-releasing factor receptor antagonists in the rat defensive burying test. Program No. 538.13. Abstract Viewer and Itinerary Planner. Washington, D.C.: Society for NeuroscienceGoogle Scholar
  20. Fu XC, Song ZF, Fu CY, Liang WQ (2005) A simple predictive model for blood-brain barrier penetration. Pharmazie 60:354–358PubMedGoogle Scholar
  21. Funk CK, O’Dell LE, Crawford EF, Koob GF (2006) Corticotropin-releasing factor within the central nucleus of the amygdala mediates enhanced ethanol self-administration in withdrawn, ethanol-dependent rats. J Neurosci 26:11324–11332PubMedCrossRefGoogle Scholar
  22. Funk CK, Zorrilla EP, Lee MJ, Rice KC, Koob GF (2007) Corticotropin-releasing factor 1 antagonists selectively reduce ethanol self-administration in ethanol-dependent rats. Biol Psychiatry 61:78–86PubMedCrossRefGoogle Scholar
  23. Gilligan PJ, Baldauf C, Cocuzza A, Chidester D, Zaczek R, Fitzgerald LW, McElroy J, Smith MA, Shen HS, Saye JA, Christ D, Trainor G, Robertson DW, Hartig P (2000) The discovery of 4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine: a corticotropin-releasing factor (hCRF1) antagonist. Bioorg Med Chem 8:181–189PubMedCrossRefGoogle Scholar
  24. Goeders NE, Bienvenu OJ, De Souza EB (1990) Chronic cocaine administration alters corticotropin-releasing factor receptors in the rat brain. Brain Res 531:322–328PubMedCrossRefGoogle Scholar
  25. Goeders NE, Guerin GF (1994) Non-contingent electric footshock facilitates the acquisition of intravenous cocaine self-administration in rats. Psychopharmacology 114:63–70PubMedCrossRefGoogle Scholar
  26. Goeders NE, Guerin GF (1996a) Effects of surgical and pharmacological adrenalectomy on the initiation and maintenance of intravenous cocaine self-administration in rats. Brain Res 722:145–152PubMedCrossRefGoogle Scholar
  27. Goeders NE, Guerin GF (1996b) Role of corticosterone in intravenous cocaine self-administration in rats. Neuroendocrinology 64:337–348PubMedGoogle Scholar
  28. Goeders NE, Guerin GF (2000) Effects of the CRH receptor antagonist CP-154,526 on intravenous cocaine self-administration in rats. Neuropsychopharmacology 23:577–586PubMedCrossRefGoogle Scholar
  29. Hauger RL, Risbrough V, Brauns O, Dautzenberg FM (2006) Corticotropin releasing factor (CRF) receptor signaling in the central nervous system: new molecular targets. CNS Neurol Disord Drug Targets 5:453–479PubMedGoogle Scholar
  30. Heilig M, Koob GF (2007) A key role for corticotropin-releasing factor in alcohol dependence. Trends Neurosci 30:399–406PubMedCrossRefGoogle Scholar
  31. Kampman KM, Volpicelli JR, McGinnis DE, Alterman AI, Weinrieb RM, D’Angelo L et al (1998) Reliability and validity of the Cocaine Selective Severity Assessment. Addict Behav 23:449–461PubMedCrossRefGoogle Scholar
  32. Kelder J, Grootenhuis PD, Bayada DM, Delbressine LP, Ploemen JP (1999) Polar molecular surface as a dominating determinant for oral absorption and brain penetration of drugs. Pharm Res 16:1514–1519PubMedCrossRefGoogle Scholar
  33. Keller C, Bruelisauer A, Lemaire M, Enz A (2002) Brain pharmacokinetics of a nonpeptidic corticotropin-releasing factor receptor antagonist. Drug Metab Dispos 30:173–176PubMedCrossRefGoogle Scholar
  34. Kitamura O, Wee S, Specio SE, Koob GF, Pulvirenti L (2007) Escalation of methamphetamine self-administration in rats: a dose-effect function. Psychopharmacology 186:48–53CrossRefGoogle Scholar
  35. Koob GF (1999a) Stress, corticotropin-releasing factor, and drug addiction. Ann N Y Acad Sci 897:27–45PubMedCrossRefGoogle Scholar
  36. Koob GF (1999b) Corticotropin-releasing factor, norepinephrine, and stress. Biol Psychiatry 46:1167–1180PubMedCrossRefGoogle Scholar
  37. Koob GF (2003) Neuroadaptive mechanisms of addiction: studies on the extended amygdala. Eur Neuropsychopharmacol 13:442–452PubMedCrossRefGoogle Scholar
  38. Koob GF, Caine SB, Parsons L, Markou A, Weiss F (1997) Opponent process model and psychostimulant addiction. Pharmacol Biochem Behav 57:513–521PubMedCrossRefGoogle Scholar
  39. Koob GF, Le Moal M (1997) Drug abuse: hedonic homeostatic dysregulation. Science 278:52–58PubMedCrossRefGoogle Scholar
  40. Koob GF, Le Moal M (2005) Plasticity of reward neurocircuitry and the ‘dark side’ of drug addiction. Nat Neurosci 8:1442–1444PubMedCrossRefGoogle Scholar
  41. Lee Y, Schulkin J, Davis M (1994) Effect of corticosterone on the enhancement of the acoustic startle reflex by corticotropin releasing factor (CRF). Brain Res 666(1):93–98PubMedCrossRefGoogle Scholar
  42. Lelas S, Wong H, Li YW, Heman KL, Ward KA, Zeller KL et al (2004) Anxiolytic-like effects of the corticotropin-releasing factor1 (CRF1) antagonist DMP904 [4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine] administered acutely or chronically at doses occupying central CRF1 receptors in rats. J Pharmacol Exp Ther 309:293–302PubMedCrossRefGoogle Scholar
  43. Li YW, Fitzgerald L, Wong H, Lelas S, Zhang G, Lindner MD et al (2005) The pharmacology of DMP696 and DMP904, non-peptidergic CRF1 receptor antagonists. CNS Drug Rev 11:21–52PubMedCrossRefGoogle Scholar
  44. Liu X, Tu M, Kelly RS, Chen C, Smith BJ (2004) Development of a computational approach to predict blood-brain barrier permeability. Drug Metab Dispos 32:132–139PubMedCrossRefGoogle Scholar
  45. Lovenberg TW, Liaw CW, Grigoriadis DE, Clevenger W, Chalmers DT, De Souza EB et al (1995) Cloning and characterization of a functionally distinct corticotropin-releasing factor receptor subtype from rat brain. Proc Natl Acad Sci U S A 92:836–840PubMedCrossRefGoogle Scholar
  46. Lu L, Liu Z, Huang M, Zhang Z (2003) Dopamine-dependent responses to cocaine depend on corticotropin-releasing factor receptor subtypes. J Neurochem 84:1378–1386PubMedCrossRefGoogle Scholar
  47. Makino S, Shibasaki T, Yamauchi N, Nishioka T, Mimoto T, Wakabayashi I et al (1999) Psychological stress increased corticotropin-releasing hormone mRNA and content in the central nucleus of the amygdala but not in the hypothalamic paraventricular nucleus in the rat. Brain Res 850:136–143PubMedCrossRefGoogle Scholar
  48. Mantsch JR, Goeders NE (1999) Ketoconazole does not block cocaine discrimination or the cocaine-induced reinstatement of cocaine-seeking behavior. Pharmacol Biochem Behav 64:65–73PubMedCrossRefGoogle Scholar
  49. Mantsch JR, Katz ES (2006) Elevation of glucocorticoids is necessary but not sufficient for the escalation of cocaine self-administration by chronic electric footshock stress in rats. Neuropsychopharmacology 32:367–376PubMedCrossRefGoogle Scholar
  50. Mantsch JR, Saphier D, Goeders NE (1998) Corticosterone facilitates the acquisition of cocaine self-administration in rats: opposite effects of the type II glucocorticoid receptor agonist dexamethasone. J Pharmacol Exp Ther 287:72–80PubMedGoogle Scholar
  51. Mantsch JR, Yuferov V, Mathieu-Kia AM, Ho A, Kreek MJ (2003) Neuroendocrine alterations in a high-dose, extended-access rat self-administration model of escalating cocaine use. Psychoneuroendocrinology 28:836–862PubMedCrossRefGoogle Scholar
  52. Marinelli M, Piazza PV (2002) Interaction between glucocorticoid hormones, stress and psychostimulant drugs. Eur J Neurosci 16:387–394PubMedCrossRefGoogle Scholar
  53. Marinelli M, Rouge-Pont F, Deroche V, Barrot M, De Jesus-Oliveira C, Le Moal M, Piazza PV (1997) Glucocorticoids and behavioral effects of psychostimulants. I: locomotor response to cocaine depends on basal levels of glucocorticoids. J Pharmacol Exp Ther 281:1392–1400PubMedGoogle Scholar
  54. McElroy JF, Ward KA, Zeller KL, Jones KW, Gilligan PJ, He L et al (2002) The CRF(1) receptor antagonist DMP696 produces anxiolytic effects and inhibits the stress-induced hypothalamic-pituitary-adrenal axis activation without sedation or ataxia in rats. Psychopharmacology 165:86–92PubMedCrossRefGoogle Scholar
  55. Mello NK, Negus SS, Rice KC, Mendelson JH (2006) Effects of the CRF(1) antagonist antalarmin on cocaine self-administration and discrimination in rhesus monkeys. Pharmacol Biochem Behav 85:744–751PubMedCrossRefGoogle Scholar
  56. Menzaghi F, Rassnick S, Heinrichs S, Baldwin H, Pich EM, Weiss F, Koob GF (1994) The role of corticotropin-releasing factor in the anxiogenic effects of ethanol withdrawal. Ann N Y Acad Sci 739:176–184PubMedCrossRefGoogle Scholar
  57. Merlo-Pich E, Lorang M, Yeganeh M, Rodriguez de Fonseca F, 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
  58. Moffett MC, Goeders NE (2007) CP-154,526, a CRF type-1 receptor antagonist, attenuates the cue-and methamphetamine-induced reinstatement of extinguished methamphetamine-seeking behavior in rats. Psychopharmacology 190:171–180PubMedCrossRefGoogle Scholar
  59. Pecina S, Schulkin J, Berridge KC (2006) Nucleus accumbens corticotropin-releasing factor increases cue-triggered motivation for sucrose reward: paradoxical positive incentive effects in stress? BMC Biol 4:8PubMedCrossRefGoogle Scholar
  60. Piazza PV, Deroche-Gamonent V, Rouge-Pont F, Le Moal M (2000) Vertical shifts in self-administration dose-response functions predict a drug-vulnerable phenotype predisposed to addiction. J Neurosci 20:4226–4232PubMedGoogle Scholar
  61. Przegalinski E, Filip M, Frankowska M, Zaniewska M, Papla I (2005) Effects of CP 154,526, a CRF1 receptor antagonist, on behavioral responses to cocaine in rats. Neuropeptides 39:525–533PubMedCrossRefGoogle Scholar
  62. 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
  63. Richter RM, Weiss F (1999) In vivo CRF release in rat amygdala is increased during cocaine withdrawal in self-administering rats. Synapse 32:254–261PubMedGoogle Scholar
  64. Rodriguez de Fonseca F, Carrera MR, Navarro M, Koob GF, Weiss F (1997) Activation of corticotropin-releasing factor in the limbic system during cannabinoid withdrawal. Science 276:2050–2054PubMedCrossRefGoogle Scholar
  65. Rosner B (1995) Fundamentals of biostatics. Duxbury, Boston, MAGoogle Scholar
  66. Sabino V, Cottone P, Koob GF, Steardo L, Lee MJ, Rice KC, Zorrilla EP (2006) Dissociation between opioid and CRF1 antagonist sensitive drinking in Sardinian alcohol-preferring rats. Psychopharmacology 189:175–186PubMedCrossRefGoogle Scholar
  67. Shepard JD, Schulkin J, Myers DA (2006) Chronically elevated corticosterone in the amygdala increases corticotropin releasing factor mRNA in the dorsolateral bed nucleus of stria terminalis following duress. Behav Brain Res 174:193–196PubMedCrossRefGoogle Scholar
  68. Sinha R, Fuse T, Aubin LR, O’Malley SS (2000) Psychological stress, drug-related cues and cocaine craving. Psychopharmacology 152:140–148PubMedCrossRefGoogle Scholar
  69. Sheskin DJ (2004) Handbook of parametric and nonparametric statistical procedures. Chapman and Hall, Boca Raton, pp 678–679Google Scholar
  70. Strickley RG (2004) Solubilizing excipients in oral and injectable formulations. Pharm Res 21:201–230PubMedCrossRefGoogle Scholar
  71. Vale W, Spiess J, Rivier C, Rivier J (1981) Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 213:1394–1397PubMedCrossRefGoogle Scholar
  72. Webster EL, Lewis DB, Torpy DJ, Zachman EK, Rice KC, Chrousos GP (1996) In vivo and in vitro characterization of antalarmin, a non-peptide corticotropin-releasing hormone (CRH) receptor antagonist: suppression of pituitary ACTH release and peripheral inflammation. Endocrinology 137:5747–5750PubMedCrossRefGoogle Scholar
  73. Wee S, Specio SE, Koob GF (2007) Effects of dose and session duration on cocaine self-administration in rats. J Pharmacol Exp Ther 320:1134–1143PubMedCrossRefGoogle Scholar
  74. 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 937:1–26PubMedCrossRefGoogle Scholar
  75. Winer BJ (1962) Statistical principles in experimental design. McGraw-Hill, New YorkGoogle Scholar
  76. Zhao YH, Abraham MH, Ibrahim A, Fish PV, Cole S, Lewis ML, de Groot MJ, Reynolds DP (2007) Predicting penetration across the blood-brain barrier from simple descriptors and fragmentation schemes. J Chem Inf Model 47:170–175PubMedCrossRefGoogle Scholar
  77. Zorrilla EP, Koob GF (2004) The therapeutic potential of CRF1 antagonists for anxiety. Expert Opin Investig Drugs 13:799–828PubMedCrossRefGoogle Scholar
  78. Zorrilla EP, Valdez GR, Weiss F (2001) Changes in levels of regional CRF-like-immunoreactivity and plasma corticosterone during protracted drug withdrawal in dependent rats. Psychopharmacology 158:374–381PubMedCrossRefGoogle Scholar
  79. 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

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Sheila E. Specio
    • 1
  • Sunmee Wee
    • 1
    Email author
  • Laura E. O’Dell
    • 2
  • Benjamin Boutrel
    • 3
  • Eric P. Zorrilla
    • 1
  • George F. Koob
    • 1
  1. 1.Committee on the Neurobiology of Addictive Disorders, SP30-2400The Scripps Research InstituteLa JollaUSA
  2. 2.Department of PsychologyThe University of Texas at El PasoEl PasoUSA
  3. 3.Center for Psychiatric Neuroscience, Department of PsychiatryUniversity of LausannePrillySwitzerland

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