, Volume 203, Issue 1, pp 121–130

Interaction between noradrenaline and corticotrophin-releasing factor in the reinstatement of cocaine seeking in the rat

  • Zenya J. Brown
  • Erin Tribe
  • Nicole A. D’souza
  • Suzanne Erb
Original Investigation



Corticotropin-releasing factor (CRF) and noradrenaline (NA) have been shown in independent studies to mediate stress-induced reinstatement of drug seeking. To date, however, a functional interaction between the systems in reinstatement has not been demonstrated.


The objectives of this study were to determine whether CRF and NA systems can interact to influence reinstatement responding and, if so, in what direction the interaction occurs.

Materials and methods

Rats were trained to self-administer cocaine (0.23 mg/kg per infusion) for 8–10 days. Subsequently, responding for drug was extinguished, and tests for reinstatement were conducted following: (1) pretreatment with the CRF receptor antagonist, d-Phe CRF12–41 [1 μg, intracerebroventricular (i.c.v.)], prior to i.c.v. injections of NA (10 μg; Experiment 1); (2) pretreatment with the α2 adrenoceptor agonist, clonidine (40 μg/kg, i.p.), prior to i.c.v. injections of CRF (0.5 μg; Experiment 2); (3) pretreatment with d-Phe (1, 5 μg, i.c.v.), prior to systemic injections of the α2 adrenoceptor antagonist, yohimbine (1.25 mg/kg; Experiment 3A); or (4) pretreatment with clonidine (40 μg/kg, i.p.) prior to systemic injections of yohimbine (0.625 mg/kg, 1.25 mg/kg; Experiment 3B).


NA reliably induced reinstatement, an effect that was blocked by pretreatment with d-Phe. In contrast, CRF-induced reinstatement was not attenuated by pretreatment with clonidine. Pretreatment with neither d-Phe nor clonidine was effective in blocking yohimbine-induced reinstatement.


Together, the present findings suggest a functional interaction between NA and CRF systems in mediating stress-induced reinstatement of cocaine seeking, whereby activation of CRF receptors occurs subsequent to, and downstream of, the sites of action of NA.


Stress Cocaine Yohimbine Relapse CRF NA 


  1. Carey RJ, DePalma G, Shanahan A, Damianopoulos EN, Müller CP, Huston JP (2008) Effects on spontaneous and cocaine-induced behavior of pharmacological inhibition of noradrenergic and serotonergic systems. Pharmacol Biochem Behav 89:54–63PubMedCrossRefGoogle Scholar
  2. Dunn AJ, Berridge CW (1990) Physiological and behavioral responses to corticotropin-releasing factor administration: is CRF a mediator of anxiety or stress responses. Brain Res Brain Res Rev 15:71–100PubMedCrossRefGoogle Scholar
  3. Dunn AJ, Swiergiel AH (2008) The role of corticotropin-releasing factor and noradrenaline in stress-related responses, and the inter-relationships between the two systems. Eur J Pharmacol 583:186–193PubMedCrossRefGoogle Scholar
  4. Dzung Le A, Funk D, Harding S, Juzytsch W, Li Z, Fletcher PJ (2008) Intra-median raphe nucleus (MRN) infusions of muscimol, a GABA-A receptor agonist, reinstate alcohol seeking in rats: role of impulsivity and reward. Psychopharmacology (Berl) 195:605–615CrossRefGoogle Scholar
  5. Eliava M, Yilmazer-Hanke D, Asan E (2003) Interrelations between monoaminergic afferents and corticotropin-releasing factor-immunoreactive neurons in the rat central amygdaloid nucleus: ultrastructural evidence for dopaminergic control of amygdaloid stress systems. Histochem Cell Biol 120:183–197PubMedCrossRefGoogle Scholar
  6. Emoto H, Tanaka M, Koga C, Yokoo H, Tsuda A, Yoshida M (1993) Corticotropin-releasing factor activates the noradrenergic neuron system in the rat brain. Pharmacol Biochem Behav 45:419–422PubMedCrossRefGoogle Scholar
  7. Erb S, Shaham Y, Stewart J (1998) The role of corticotropin-releasing factor and corticosterone in stress- and cocaine-induced relapse to cocaine seeking in rats. J Neurosci 18:5529–5536PubMedGoogle Scholar
  8. Erb S, Stewart J (1999) A role for the bed nucleus of the stria terminalis, but not the amygdala, in the effects of corticotropin-releasing factor on stress-induced reinstatement of cocaine seeking. J Neurosci 19:RC35PubMedGoogle Scholar
  9. Erb S, Hitchcott PK, Rajabi H, Mueller D, Shaham Y, Stewart J (2000) Alpha-2 adrenergic receptor agonists block stress-induced reinstatement of cocaine seeking. Neuropsychopharmacology 23:138–150PubMedCrossRefGoogle Scholar
  10. Erb S, Salmaso N, Rodaros D, Stewart J (2001a) 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 (Berl) 158:360–365CrossRefGoogle Scholar
  11. Erb S, Shaham Y, Stewart J (2001b) Stress-induced relapse to drug seeking in the rat: role of the bed nucleus of the stria terminalis and amygdala. Stress 4:289–303Google Scholar
  12. 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 (Berl) 187:112–120CrossRefGoogle Scholar
  13. Feltenstein MW, See RE (2006) Potentiation of cue-induced reinstatement of cocaine-seeking in rats by the anxiogenic drug yohimbine. Behav Brain Res 174:1–8PubMedCrossRefGoogle Scholar
  14. Fletcher PJ, Rizos Z, Sinyard J, Tampakeras M, Higgins GA (2008) The 5-HT2C receptor agonist Ro60-0175 reduces cocaine self-administration and reinstatement induced by the stressor yohimbine, and contextual cues. Neuropsychopharmacology 33:1402–1412PubMedCrossRefGoogle Scholar
  15. Ghitza UE, Gray SM, Epstein DH, Rice KC, Shaham Y (2006) The anxiogenic drug yohimbine reinstates palatable food seeking in a rat relapse model: a role of CRF1 receptors. Neuropsychopharmacology 31:2188–2196PubMedGoogle Scholar
  16. Gorman AL, Dunn AJ (1993) Beta-adrenergic receptors are involved in stress-related behavioral changes. Pharmacol Biochem Behav 45:1–7PubMedCrossRefGoogle Scholar
  17. Koob GF (1999) Corticotropin-releasing factor, norepinephrine, and stress. Biol Psychiatry 46:1167–1180PubMedCrossRefGoogle Scholar
  18. Le AD, Harding S, Juzytsch W, Watchus J, Shalev U, Shaham Y (2000) The role of corticotrophin-releasing factor in stress-induced relapse to alcohol-seeking behavior in rats. Psychopharmacology (Berl) 150:317–324CrossRefGoogle Scholar
  19. Le AD, Harding S, Juzytsch W, Fletcher PJ, Shaham Y (2002) The role of corticotropin-releasing factor in the median raphe nucleus in relapse to alcohol. J Neurosci 22:7844–7849PubMedGoogle Scholar
  20. Lee B, Tiefenbacher S, Platt DM, Spealman RD (2004) Pharmacological blockade of alpha2-adrenoceptors induces reinstatement of cocaine-seeking behavior in squirrel monkeys. Neuropsychopharmacology 29:686–693PubMedCrossRefGoogle Scholar
  21. Le AD, Harding S, Juzytsch W, Funk D, Shaham Y (2005) Role of alpha-2 adrenoceptors in stress-induced reinstatement of alcohol seeking and alcohol self-administration in rats. Psychopharmacology (Berl) 179:366–373CrossRefGoogle Scholar
  22. Leri F, Flores J, Rodaros D, Stewart J (2002) Blockade of stress-induced but not cocaine-induced reinstatement by infusion of noradrenergic antagonists into the bed nucleus of the stria terminalis or the central nucleus of the amygdala. J Neurosci 22:5713–5718PubMedGoogle Scholar
  23. Li J, Takeda H, Tsuji M, Liu L, Matsumiya T (1998) Antagonism of central CRF systems mediates stress-induced changes in noradrenaline and serotonin turnover in rat brain regions. Methods Find Exp Clin Pharmacol 20:409–417PubMedCrossRefGoogle Scholar
  24. Lu L, Shepard JD, Scott Hall F, Shaham Y (2003) Effect of environmental stressors on opiate and psychostimulant reinforcement, reinstatement and discrimination in rats: a review. Neurosci Biobehav Rev 27:457–491PubMedCrossRefGoogle Scholar
  25. Mantsch JR, Baker DA, Francis DM, Katz ES, Hoks MA, Serge JP (2008) Stressor- and corticotropin releasing factor-induced reinstatement and active stress-related behavioral responses are augmented following long-access cocaine self-administration by rats. Psychopharmacology (Berl) 195:591–603CrossRefGoogle Scholar
  26. Marinelli PW, Funk D, Juzytsch W, Harding S, Rice KC, Shaham Y, Le AD (2007) The CRF1 receptor antagonist antalarmin attenuates yohimbine-induced increases in operant alcohol self-administration and reinstatement of alcohol seeking in rats. Psychopharmacology (Berl) 195:345–355CrossRefGoogle Scholar
  27. Millan MJ, Newman-Tancredi A, Audinot V, Cussac D, Lejeune F, Nicolas JP, Coge F, Galizzi JP, Boutin JA, Rivet JM, Dekeyne A, Gobert A (2000) Agonist and antagonist actions of yohimbine as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Synapse 35:79–95PubMedCrossRefGoogle Scholar
  28. Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates, 3rd edn. Academic Press, Academic PressGoogle Scholar
  29. Phelix CF, Liposits Z, Paull WK (1994) Catecholamine-CRF synaptic interaction in a septal bed nucleus: afferents of neurons in the bed nucleus of the stria terminalis. Brain Res Bull 33:109–119PubMedCrossRefGoogle Scholar
  30. Platt DM, Rowlett JK, Spealman RD (2007) Noradrenergic mechanisms in cocaine-induced reinstatement of drug seeking in squirrel monkeys. J Pharmacol Exp Ther 322:894–902PubMedCrossRefGoogle Scholar
  31. Rodaros D, Caruana DA, Amir S, Stewart J (2007) Corticotropin-releasing factor projections from limbic forebrain and paraventricular nucleus of the hypothalamus to the region of the ventral tegmental area. Neuroscience 150:8–13PubMedCrossRefGoogle Scholar
  32. Sakai R, Ma L, He P, Fluharty S (1995) Intracerebraoventricular administration of angiotensin type 1 (AT1) receptor antisense oligonucleotides attenuate thirst in the rat. Regulatory Peptides 59:183–192PubMedCrossRefGoogle Scholar
  33. Sakanaka M, Shibasaki T, Lederis K (1986) Distribution and efferent projections of corticotropin-releasing factor-like immunoreactivity in the rat amygdaloid complex. Brain Res 382:213–238PubMedCrossRefGoogle Scholar
  34. Sarnyai Z, Shaham Y, Heinrichs SC (2001) The role of corticotropin-releasing factor in drug addiction. Pharmacol Rev 53:209–243PubMedGoogle Scholar
  35. Schmidt HD, Pierce RC (2006) Systemic administration of a dopamine, but not a serotonin or norepinephrine, transporter inhibitor reinstates cocaine seeking in the rat. Behav Brain Res 175:189–194PubMedCrossRefGoogle Scholar
  36. Shaham Y, Funk D, Erb S, Brown TJ, Walker CD, Stewart J (1997) Corticotropin-releasing factor, but not corticosterone, is involved in stress-induced relapse to heroin-seeking in rats. J Neurosci 17:2605–2614PubMedGoogle Scholar
  37. Shaham Y, Erb S, Leung S, Buczek Y, Stewart J (1998) CP-154,526, a selective, non-peptide antagonist of the corticotropin-releasing factor1 receptor attenuates stress-induced relapse to drug seeking in cocaine- and heroin-trained rats. Psychopharmacology (Berl) 137:184–190CrossRefGoogle Scholar
  38. Shaham Y, Erb S, Stewart J (2000a) Stress-induced relapse to heroin and cocaine seeking in rats: a review. Brain Res Brain Res Rev 33:13–33PubMedCrossRefGoogle Scholar
  39. Shaham Y, Highfield D, Delfs J, Leung S, Stewart J (2000b) Clonidine blocks stress-induced reinstatement of heroin seeking in rats: an effect independent of locus coeruleus noradrenergic neurons. Eur J Neurosci 12:292–302PubMedCrossRefGoogle Scholar
  40. Shepard JD, Bossert JM, Liu SY, Shaham Y (2004) The anxiogenic drug yohimbine reinstates methamphetamine seeking in a rat model of drug relapse. Biol Psychiatry 55:1082–1089PubMedCrossRefGoogle Scholar
  41. Sinha R, Talih M, Malison R, Cooney N, Anderson GM, Kreek MJ (2003) Hypothalamic-pituitary-adrenal axis and sympatho-adreno-medullary responses during stress-induced and drug cue-induced cocaine craving states. Psychopharmacology (Berl) 170:62–72CrossRefGoogle Scholar
  42. Stewart J (2003) Stress and relapse to drug seeking: studies in laboratory animals shed light on mechanisms and sources of long-term vulnerability. Am J Addict 12:1–17PubMedCrossRefGoogle Scholar
  43. Valentino R, Page M, Curtis A (1991) Activation of noradrenergic locus coeruleus neurons by hemodynamic stress is due to local release of corticotropin-releasing factor. Brain Res. 555:25–34PubMedCrossRefGoogle Scholar
  44. Valentino RJ, Foote SL, Page ME (1993) The locus coeruleus as a site for integrating corticotropin-releasing factor and noradrenergic mediation of stress responses. Ann N Y Acad Sci 697:173–188PubMedCrossRefGoogle Scholar
  45. Wang B, You ZB, Rice KC, Wise RA (2007) Stress-induced relapse to cocaine seeking: roles for the CRF(2) receptor and CRF-binding protein in the ventral tegmental area of the rat. Psychopharmacology (Berl) 193:283–294CrossRefGoogle Scholar
  46. Yang XM, Dunn AJ (1990) Central beta 1-adrenergic receptors are involved in CRF-induced defensive withdrawal. Pharmacol Biochem Behav 36:847–851PubMedCrossRefGoogle Scholar
  47. Zislis G, Desai TV, Prado M, Shah HP, Bruijnzeel AW (2007) Effects of the CRF receptor antagonist D-Phe CRF(12-41) and the alpha2-adrenergic receptor agonist clonidine on stress-induced reinstatement of nicotine-seeking behavior in rats. Neuropharmacol 53:958–966CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Zenya J. Brown
    • 1
  • Erin Tribe
    • 1
  • Nicole A. D’souza
    • 1
  • Suzanne Erb
    • 1
  1. 1.Centre for the Neurobiology of Stress, Department of PsychologyUniversity of Toronto ScarboroughTorontoCanada

Personalised recommendations