, Volume 234, Issue 18, pp 2813–2821 | Cite as

Prevention and reversal of social stress-escalated cocaine self-administration in mice by intra-VTA CRFR1 antagonism

  • Xiao Han
  • Joseph F. DeBold
  • Klaus A. Miczek
Original Investigation



A history of brief intermittent social defeat stress can escalate cocaine self-administration and induce long-term adaptations in the mesolimbic dopamine system. Extra-hypothalamic corticotrophin releasing factor (CRF) has been shown to be closely associated with stress-induced escalation of drug use. How repeated stress modulates CRF release in the ventral tegmental area (VTA) and the roles of CRF receptors during different phases of stress-induced cocaine self-administration remain to be defined.


The current study examines the roles of CRF and CRF receptor 1 (CRFR1) in escalated intravenous cocaine self-administration after exposure to social defeat stress in mice.

Methods and results

First, CRFR1 antagonist (CP 376,395, 15 mg/kg, i.p.) given 30 min prior to each social defeat episode prevented later escalated cocaine self-administration. When CP 376,395 (5 and 15 mg/kg, i.p.) was administered 10 days after the last episode of social stress, the escalation of cocaine intake was dose-dependently reversed. Moreover, socially defeated mice showed increased CRF release in the VTA compared to controls. To further explore the role of CRFR1, CP 376,395 (0.5 and 1 μg/0.2 μl) was infused directly into the VTA before the cocaine self-administration session. Intra-VTA antagonism of CRFR1 was sufficient to reverse social defeat stress-escalated cocaine self-administration.


These findings suggest that CRF and CRFR1 exert multiple roles in the response to social stress that are relevant to escalated cocaine self-administration.


Social defeat stress CRF microdialysis CRFR1 Intravenous cocaine self-administration Microinjection VTA Mice 



This research was supported by National Institute on Drug Abuse Grant DA031734, KAM, PI.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.


  1. Albrechet-Souza L, Hwa LS, Han X, Zhang EY, DeBold JF, Miczek KA (2015) Corticotropin releasing factor binding protein and CRF2 receptors in the ventral tegmental area: modulation of ethanol binge drinking in C57BL/6J mice. Alcohol Clin Exp Res 39:1609–1618CrossRefPubMedPubMedCentralGoogle Scholar
  2. Björkqvist K (2001) Social defeat as a stressor in humans. Physiol Behav 73:435–442CrossRefPubMedGoogle Scholar
  3. Blacktop JM, Seubert C, Baker DA, Ferda N, Lee G, Graf EN, Mantsch JR (2011) Augmented cocaine seeking in response to stress or CRF delivered into the ventral tegmental area following long-access self-administration is mediated by CRF receptor type 1 but not CRF receptor type 2. J Neurosci 31:11396–11403CrossRefPubMedPubMedCentralGoogle Scholar
  4. Borgland SL, Ungless MA, Bonci A (2010) Convergent actions of orexin/hypocretin and CRF on dopamine neurons: emerging players in addiction. Brain Res 1314:139–144CrossRefPubMedGoogle Scholar
  5. Bossert JM, Marchant NJ, Calu DJ, Shaham Y (2013) The reinstatement model of drug relapse: recent neurobiological findings, emerging research topics, and translational research. Psychopharmacology 229:453–476CrossRefPubMedPubMedCentralGoogle Scholar
  6. Boyson CO, Holly EN, Shimamoto A, Albrechet-Souza L, Weiner LA, DeBold JF, Miczek KA (2014) Social stress and CRF-dopamine interactions in the VTA: role in long-term escalation of cocaine self-administration. J Neurosci 34:6659–6667CrossRefPubMedPubMedCentralGoogle Scholar
  7. Boyson CO, Miguel TT, Quadros IM, DeBold JF, Miczek KA (2011) Prevention of social stress-escalated cocaine self-administration by CRF-R1 antagonist in the rat VTA. Psychopharmacology 218:257–269CrossRefPubMedPubMedCentralGoogle Scholar
  8. Charlton BG, Ferrier IN, Perry RH (1987) Distribution of corticotropin-releasing factor-like immunoreactivity in human brain. Neuropeptides 10:329–334CrossRefPubMedGoogle Scholar
  9. Covington HE III, Miczek KA (2001) Repeated social-defeat stress, cocaine or morphine. Effects on behavioral sensitization and intravenous cocaine self-administration “binges”. Psychopharmacology 158:388–398CrossRefPubMedGoogle Scholar
  10. 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
  11. Curtis AL, Pavcovich LA, Grigoriadis DE, Valentino RJ (1995) Previous stress alters corticotropin-releasing factor neurotransmission in the locus coeruleus. Neuroscience 65:541–550CrossRefPubMedGoogle Scholar
  12. Goeders NE, Guerin GF (2000) Effects of the CRH receptor antagonist CP-154,526 on intravenous cocaine self-administration in rats. Neuropsychopharmacology 23:577–586CrossRefPubMedGoogle Scholar
  13. Han X, Albrechet-Souza L, Doyle MR, Shimamoto A, DeBold JF, Miczek KA (2015) Social stress and escalated drug self-administration in mice II. Cocaine and dopamine in the nucleus accumbens. Psychopharmacology (Berl) 232:1003–1010CrossRefGoogle Scholar
  14. 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 5:453–479CrossRefPubMedPubMedCentralGoogle Scholar
  15. Heilig M, Koob GF (2007) A key role for corticotropin-releasing factor in alcohol dependence. Trends Neurosci 30:399–406CrossRefPubMedPubMedCentralGoogle Scholar
  16. Holly EN, Boyson CO, Montagud-Romero S, Stein DJ, Gobrogge KL, DeBold JF, Miczek KA (2016) Episodic social stress-escalated cocaine self-administration: role of phasic and tonic corticotropin releasing factor in the anterior and posterior ventral tegmental area. J Neurosci 36:4093–4105CrossRefPubMedPubMedCentralGoogle Scholar
  17. Holmes A, Heilig M, Rupniak NM, Steckler T, Griebel G (2003) Neuropeptide systems as novel therapeutic targets for depression and anxiety disorders. Trends Pharmacol Sci 24:580–588CrossRefPubMedGoogle Scholar
  18. Koob GF (2010) The role of CRF and CRF-related peptides in the dark side of addiction. Brain Res 1314:3–14CrossRefPubMedGoogle Scholar
  19. Koob GF, Zorrilla EP (2010) Neurobiological mechanisms of addiction: focus on corticotropin-releasing factor. Curr Opin Investig Drugs 11:63–71PubMedPubMedCentralGoogle Scholar
  20. Korotkova TM, Brown RE, Sergeeva OA, Ponomarenko AA, Haas HL (2006) Effects of arousal- and feeding-related neuropeptides on dopaminergic and GABAergic neurons in the ventral tegmental area of the rat. Eur J Neurosci 23:2677–2685CrossRefPubMedGoogle Scholar
  21. Kwako LE, Spagnolo PA, Schwandt ML, Thorsell A, George DT, Momenan R et al (2015) The corticotropin releasing hormone-1 (CRH1) receptor antagonist pexacerfont in alcohol dependence: a randomized controlled experimental medicine study. Neuropsychopharmacology 40:1053–1063CrossRefPubMedGoogle Scholar
  22. Mantsch JR, Baker DA, Funk D, Le AD, Shaham Y (2016) Stress-induced reinstatement of drug seeking: 20 years of progress. Neuropsychopharmacology 41:335–356CrossRefPubMedGoogle Scholar
  23. Manvich DF, Stowe TA, Godfrey JR, Weinshenker D (2016) A method for psychosocial stress-induced reinstatement of cocaine seeking in rats. Biol Psychiatry 79:940–946CrossRefPubMedGoogle Scholar
  24. Miczek KA, Nikulina EM, Shimamoto A, Covington HE III (2011) Escalated or suppressed cocaine reward, tegmental BDNF and accumbal dopamine due to episodic vs. continuous social stress in rats. J Neurosci 31:9848–9857CrossRefPubMedPubMedCentralGoogle Scholar
  25. Miczek KA, O'Donnell JM (1978) Intruder-evoked aggression in isolated and nonisolated mice: effects of psychomotor stimulants and L-dopa. Psychopharmacology 57:47–55CrossRefPubMedGoogle Scholar
  26. Miczek KA, Thompson ML, Shuster L (1982) Opioid-like analgesia in defeated mice. Science 215:1520–1522CrossRefPubMedGoogle Scholar
  27. Miczek KA, Yap JJ, Covington HE III (2008) Social stress, therapeutics and drug abuse: preclinical models of escalated and depressed intake. Pharmacol Ther 120:102–128CrossRefPubMedPubMedCentralGoogle Scholar
  28. National Research Council (2011) Guide for the care and use of laboratory animals, Eighth edn. National Academy Press, Washington DCGoogle Scholar
  29. Paxinos G, Franklin KBJ (2001) The mouse brain in stereotaxic coordinates, Second edn. Academic Press, San DiegoGoogle Scholar
  30. Piazza PV, Le Moal M (1998) The role of stress in drug self-administration. Trends Pharmacol Sci 19:67–74CrossRefPubMedGoogle Scholar
  31. Quadros IM, Miczek KA (2009) Two modes of intense cocaine bingeing: increased persistence after social defeat stress and increased rate of intake due to extended access conditions in rats. Psychopharmacology 206:109–121CrossRefPubMedPubMedCentralGoogle Scholar
  32. Richter RM, Pich EM, Koob GF, Weiss F (1995) Sensitization of cocaine-stimulated increase in extracellular levels of corticotropin-releasing factor from the rat amygdala after repeated administration as determined by intracranial microdialysis. Neurosci Lett 187:169–172CrossRefPubMedGoogle Scholar
  33. Sarnyai Z, Shaham Y, Heinrichs SC (2001) The role of corticotropin-releasing factor in drug addiction. Pharmacol Rev 53:209–243PubMedGoogle Scholar
  34. Schwandt ML, Cortes CR, Kwako LE, George DT, Momenan R, Sinha R et al (2016) The CRF1 antagonist verucerfont in anxious alcohol-dependent women: translation of neuroendocrine, but not of anti-craving effects. Neuropsychopharmacology 41:2818–2829CrossRefPubMedGoogle Scholar
  35. Shaham Y, de Wit H (2016) Lost in translation: CRF1 receptor antagonists and addiction treatment. Neuropsychopharmacology 41(12):2795–2797CrossRefPubMedGoogle 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. Sinha R (2001) How does stress increase risk of drug abuse and relapse? Psychopharmacology 158:343–359CrossRefPubMedGoogle Scholar
  38. Sinha R (2008) Chronic stress, drug use, and vulnerability to addiction. Ann N Y Acad Sci 1141:105–130CrossRefPubMedPubMedCentralGoogle Scholar
  39. Snyder K, Wang WW, Han R, McFadden K, Valentino RJ (2012) Corticotropin-releasing factor in the norepinephrine nucleus, locus coeruleus, facilitates behavioral flexibility. Neuropsychopharmacology 37:520–530CrossRefPubMedGoogle Scholar
  40. Swanson LW, Sawchenko PE, Rivier J, Vale WW (1983) Organization of ovine corticotropin-releasing factor immunoreactive cells and fibers in the rat brain: an immunohistochemical study. Neuroendocrinology 36:165–186CrossRefPubMedGoogle Scholar
  41. Vaughan J, Donaldson C, Bittencourt J, Perrin MH, Lewis K, Sutton S, Chan R, Turnbull AV, Lovejoy D, Rivier C (1995) Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature 378:287–292CrossRefPubMedGoogle Scholar
  42. Wanat MJ, Hopf FW, Stuber GD, Phillips PE, Bonci A (2008) Corticotropin-releasing factor increases mouse ventral tegmental area dopamine neuron firing through a protein kinase C-dependent enhancement of Ih. J Physiol 586:2157–2170CrossRefPubMedPubMedCentralGoogle Scholar
  43. Wang B, Shaham Y, Zitzman D, Azari S, Wise RA, You ZB (2005) Cocaine experience establishes control of midbrain glutamate and dopamine by corticotropin-releasing factor: a role in stress-induced relapse to drug seeking. J Neurosci 25:5389–5396CrossRefPubMedGoogle Scholar
  44. Wise RA, Rompre PP (1989) Brain dopamine and reward. Annu Rev Psychol 40:191–225CrossRefPubMedGoogle Scholar
  45. Wise RA (1996) Neurobiology of addiction. Curr Opin Neurobiol 6(2):243–251CrossRefPubMedGoogle Scholar
  46. Yap JJ, Miczek KA (2007) Social defeat stress, sensitization, and intravenous cocaine self-administration in mice. Psychopharmacology 192:261–273CrossRefPubMedGoogle Scholar
  47. Zorrilla EP, Heilig M, de Wit H, Shaham Y (2013) Behavioral, biological, and chemical perspectives on targeting CRF(1) receptor antagonists to treat alcoholism. Drug Alcohol Depend 128:175–186CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Xiao Han
    • 1
    • 2
  • Joseph F. DeBold
    • 1
  • Klaus A. Miczek
    • 1
    • 3
  1. 1.Department of PsychologyTufts UniversityMedfordUSA
  2. 2.Department of GeneticsHarvard Medical SchoolBostonUSA
  3. 3.Departments of Neuroscience, Pharmacology and PsychiatryTufts UniversityBostonUSA

Personalised recommendations