Corticotropin-Releasing Factor (CRF) Neurocircuitry and Neuropharmacology in Alcohol Drinking

  • Allyson L. Schreiber
  • Nicholas W. GilpinEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 248)


Alcohol use is pervasive in the United States. In the transition from nonhazardous drinking to hazardous drinking and alcohol use disorder, neuroadaptations occur within brain reward and brain stress systems. One brain signaling system that has received much attention in animal models of excessive alcohol drinking and alcohol dependence is corticotropin-releasing factor (CRF). The CRF system is composed of CRF, the urocortins, CRF-binding protein, and two receptors – CRF type 1 and CRF type 2. This review summarizes how acute, binge, and chronic alcohol dysregulates CRF signaling in hypothalamic and extra-hypothalamic brain regions and how this dysregulation may contribute to changes in alcohol reinforcement, excessive alcohol consumption, symptoms of negative affect during withdrawal, and alcohol relapse. In addition, it summarizes clinical work examining CRF type 1 receptor antagonists in humans and discusses why the brain CRF system is still relevant in alcohol research.


Alcohol dependence Alcohol use disorder Binge drinking Corticotropin-releasing factor Urocortin 


  1. Adinoff B, Iranmanesh A, Veldhuis J, Fisher L (1998) Disturbances of the stress response: the role of the HPA axis during alcohol withdrawal and abstinence. Alcohol Health Res World 22(1):67–72PubMedPubMedCentralGoogle Scholar
  2. 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(9):1609–1618. PubMedPubMedCentralCrossRefGoogle Scholar
  3. Bachtell RK, Weitemier AZ, Ryabinin AE (2004) Lesions of the Edinger-Westphal nucleus in C57BL/6J mice disrupt ethanol-induced hypothermia and ethanol consumption. Eur J Neurosci 20(6):1613–1623. PubMedCrossRefGoogle Scholar
  4. Bajo M, Cruz MT, Siggins GR, Messing R, Roberto M (2008) Protein kinase C epsilon mediation of CRF- and ethanol-induced GABA release in central amygdala. Proc Natl Acad Sci U S A 105(24):8410–8415. PubMedPubMedCentralCrossRefGoogle 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(2):227–232PubMedCrossRefGoogle Scholar
  6. Bell SM, Reynolds JG, Thiele TE, Gan J, Figlewicz DP, Woods SC (1998) Effects of third intracerebroventricular injections of corticotropin-releasing factor (CRF) on ethanol drinking and food intake. Psychopharmacology 139(1–2):128–135PubMedCrossRefGoogle Scholar
  7. Binneman B, Feltner D, Kolluri S, Shi Y, Qiu R, Stiger T (2008) A 6-week randomized, placebo-controlled trial of CP-316,311 (a selective CRH1 antagonist) in the treatment of major depression. Am J Psychiatry 165(5):617–620. PubMedCrossRefGoogle Scholar
  8. Bittencourt JC, Sawchenko PE (2000) Do centrally administered neuropeptides access cognate receptors?: an analysis in the central corticotropin-releasing factor system. J Neurosci 20(3):1142–1156PubMedCrossRefGoogle Scholar
  9. Bittencourt JC, Vaughan J, Arias C, Rissman RA, Vale WW, Sawchenko PE (1999) Urocortin expression in rat brain: evidence against a pervasive relationship of urocortin-containing projections with targets bearing type 2 CRF receptors. J Comp Neurol 415(3):285–312PubMedCrossRefGoogle Scholar
  10. Blaine SK, Milivojevic V, Fox H, Sinha R (2016) Alcohol effects on stress pathways: impact on craving and relapse risk. Can J Psychiatr 61(3):145–153. CrossRefGoogle Scholar
  11. Breese GR, Knapp DJ, Overstreet DH (2004) Stress sensitization of ethanol withdrawal-induced reduction in social interaction: inhibition by CRF-1 and benzodiazepine receptor antagonists and a 5-HT1A-receptor agonist. Neuropsychopharmacology 29(3):470–482. PubMedPubMedCentralCrossRefGoogle Scholar
  12. Cador M, Ahmed SH, Koob GF, Le Moal M, Stinus L (1992) Corticotropin-releasing factor induces a place aversion independent of its neuroendocrine role. Brain Res 597(2):304–309PubMedCrossRefGoogle Scholar
  13. Center for Behavioral Health Statistics and Quality (CBHSQ) (2016) Key substance use and mental health indicators in the United States: results from the 2015 National Survey on Drug Use and Health (HHS Publication No. SMA 16-4984, NSDUH Series H-51).
  14. Chalmers DT, Lovenberg TW, De Souza EB (1995) Localization of novel corticotropin-releasing factor receptor (CRF2) mRNA expression to specific subcortical nuclei in rat brain: comparison with CRF1 receptor mRNA expression. J Neurosci 15(10):6340–6350PubMedCrossRefGoogle Scholar
  15. Chan RK, Vale WW, Sawchenko PE (2000) Paradoxical activational effects of a corticotropin-releasing factor-binding protein “ligand inhibitor” in rat brain. Neuroscience 101(1):115–129PubMedCrossRefGoogle Scholar
  16. Chen Z, Du JZ (1996) Hypoxia effects on hypothalamic corticotropin-releasing hormone and anterior pituitary cAMP. Zhongguo Yao Li Xue Bao 17(6):489–492PubMedGoogle Scholar
  17. Chen A, Zorrilla E, Smith S, Rousso D, Levy C, Vaughan J, Donaldson C, Roberts A, Lee KF, Vale W (2006) Urocortin 2-deficient mice exhibit gender-specific alterations in circadian hypothalamus-pituitary-adrenal axis and depressive-like behavior. J Neurosci 26(20):5500–5510. PubMedCrossRefPubMedCentralGoogle Scholar
  18. Chester JA, Cunningham CL (1998) Modulation of corticosterone does not affect the acquisition or expression of ethanol-induced conditioned place preference in DBA/2J mice. Pharmacol Biochem Behav 59(1):67–75PubMedCrossRefGoogle Scholar
  19. Chou SP, Pickering RP (1992) Early onset of drinking as a risk factor for lifetime alcohol-related problems. Br J Addict 87(8):1199–1204PubMedCrossRefGoogle Scholar
  20. Chu K, Koob GF, Cole M, Zorrilla EP, Roberts AJ (2007) Dependence-induced increases in ethanol self-administration in mice are blocked by the CRF1 receptor antagonist antalarmin and by CRF1 receptor knockout. Pharmacol Biochem Behav 86(4):813–821. PubMedPubMedCentralCrossRefGoogle Scholar
  21. Cippitelli A, Damadzic R, Hamelink C, Brunnquell M, Thorsell A, Heilig M, Eskay RL (2014) Binge-like ethanol consumption increases corticosterone levels and neurodegeneration whereas occupancy of type II glucocorticoid receptors with mifepristone is neuroprotective. Addict Biol 19(1):27–36. PubMedCrossRefGoogle Scholar
  22. Coric V, Feldman HH, Oren DA, Shekhar A, Pultz J, Dockens RC, Wu X, Gentile KA, Huang SP, Emison E, Delmonte T, D'Souza BB, Zimbroff DL, Grebb JA, Goddard AW, Stock EG (2010) Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder. Depress Anxiety 27(5):417–425. PubMedCrossRefGoogle Scholar
  23. Cruz MT, Herman MA, Kallupi M, Roberto M (2012) Nociceptin/orphanin FQ blockade of corticotropin-releasing factor-induced gamma-aminobutyric acid release in central amygdala is enhanced after chronic ethanol exposure. Biol Psychiatry 71(8):666–676. PubMedCrossRefGoogle Scholar
  24. Dabrowska J, Hazra R, Guo JD, Dewitt S, Rainnie DG (2013a) Central CRF neurons are not created equal: phenotypic differences in CRF-containing neurons of the rat paraventricular hypothalamus and the bed nucleus of the stria terminalis. Front Neurosci 7:156. PubMedPubMedCentralCrossRefGoogle Scholar
  25. Dabrowska J, Hazra R, Guo JD, Li C, Dewitt S, Xu J, Lombroso PJ, Rainnie DG (2013b) Striatal-enriched protein tyrosine phosphatase-STEPs toward understanding chronic stress-induced activation of corticotrophin releasing factor neurons in the rat bed nucleus of the stria terminalis. Biol Psychiatry 74(11):817–826. PubMedCrossRefGoogle Scholar
  26. Dabrowska J, Martinon D, Moaddab M, Rainnie DG (2016) Targeting corticotropin-releasing factor projections from the oval nucleus of the bed nucleus of the stria terminalis using cell-type specific neuronal tracing studies in mouse and rat brain. J Neuroendocrinol 28(12).
  27. Deas D, Brown ES (2006) Adolescent substance abuse and psychiatric comorbidities. J Clin Psychiatry 67(7):e02PubMedCrossRefGoogle Scholar
  28. Dunlop BW, Binder EB, Iosifescu D, Mathew SJ, Neylan TC, Pape JC, Carrillo-Roa T, Green C, Kinkead B, Grigoriadis D, Rothbaum BO, Nemeroff CB, Mayberg HS (2017) Corticotropin-releasing factor receptor 1 antagonism is ineffective for women with posttraumatic stress disorder. Biol Psychiatry.
  29. 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 Rev 15(2):71–100PubMedCrossRefGoogle Scholar
  30. Edwards S, Vendruscolo LF, Schlosburg JE, Misra KK, Wee S, Park PE, Schulteis G, Koob GF (2012) Development of mechanical hypersensitivity in rats during heroin and ethanol dependence: alleviation by CRF(1) receptor antagonism. Neuropharmacology 62(2):1142–1151. PubMedCrossRefGoogle Scholar
  31. Eisenhardt M, Hansson AC, Spanagel R, Bilbao A (2015) Chronic intermittent ethanol exposure in mice leads to an up-regulation of CRH/CRHR1 signaling. Alcohol Clin Exp Res 39(4):752–762. PubMedCrossRefGoogle Scholar
  32. Fekete EM, Zorrilla EP (2007) Physiology, pharmacology, and therapeutic relevance of urocortins in mammals: ancient CRF paralogs. Front Neuroendocrinol 28(1):1–27. PubMedCrossRefGoogle Scholar
  33. Finn DA, Snelling C, Fretwell AM, Tanchuck MA, Underwood L, Cole M, Crabbe JC, Roberts AJ (2007) Increased drinking during withdrawal from intermittent ethanol exposure is blocked by the CRF receptor antagonist D-Phe-CRF(12-41). Alcohol Clin Exp Res 31(6):939–949. PubMedCrossRefGoogle Scholar
  34. Fleck BA, Hoare SR, Pick RR, Bradbury MJ, Grigoriadis DE (2012) Binding kinetics redefine the antagonist pharmacology of the corticotropin-releasing factor type 1 receptor. J Pharmacol Exp Ther 341(2):518–531. PubMedCrossRefGoogle Scholar
  35. Francesconi W, Berton F, Repunte-Canonigo V, Hagihara K, Thurbon D, Lekic D, Specio SE, Greenwell TN, Chen SA, Rice KC, Richardson HN, O'Dell LE, Zorrilla EP, Morales M, Koob GF, Sanna PP (2009) Protracted withdrawal from alcohol and drugs of abuse impairs long-term potentiation of intrinsic excitability in the juxtacapsular bed nucleus of the stria terminalis. J Neurosci 29(17):5389–5401. PubMedPubMedCentralCrossRefGoogle Scholar
  36. Funk CK, Koob GF (2007) A CRF(2) agonist administered into the central nucleus of the amygdala decreases ethanol self-administration in ethanol-dependent rats. Brain Res 1155:172–178. PubMedPubMedCentralCrossRefGoogle Scholar
  37. Funk D, Li Z, Le AD (2006) Effects of environmental and pharmacological stressors on c-fos and corticotropin-releasing factor mRNA in rat brain: relationship to the reinstatement of alcohol seeking. Neuroscience 138(1):235–243. PubMedCrossRefGoogle Scholar
  38. 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(1):78–86. PubMedCrossRefGoogle Scholar
  39. Funk D, Coen K, Le AD (2014) The role of kappa opioid receptors in stress-induced reinstatement of alcohol seeking in rats. Brain Behav 4(3):356–367. PubMedPubMedCentralCrossRefGoogle Scholar
  40. Galesi FL, Ayanwuyi LO, Mijares MG, Cippitelli A, Cannella N, Ciccocioppo R, Ubaldi M (2016) Role of hypothalamic-pituitary-adrenal axis and corticotropin-releasing factor stress system on cue-induced relapse to alcohol seeking. Eur J Pharmacol 788:84–89. PubMedPubMedCentralCrossRefGoogle Scholar
  41. Gehlert DR, Cippitelli A, Thorsell A, Le AD, Hipskind PA, Hamdouchi C, Lu J, Hembre EJ, Cramer J, Song M, McKinzie D, Morin M, Ciccocioppo R, Heilig M (2007) 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo [1,2-b]pyridazine: a novel brain-penetrant, orally available corticotropin-releasing factor receptor 1 antagonist with efficacy in animal models of alcoholism. J Neurosci 27(10):2718–2726. PubMedCrossRefPubMedCentralGoogle Scholar
  42. George O, Sanders C, Freiling J, Grigoryan E, Vu S, Allen CD, Crawford E, Mandyam CD, Koob GF (2012) Recruitment of medial prefrontal cortex neurons during alcohol withdrawal predicts cognitive impairment and excessive alcohol drinking. Proc Natl Acad Sci U S A 109(44):18156–18161. PubMedPubMedCentralCrossRefGoogle Scholar
  43. Giardino WJ, Cocking DL, Kaur S, Cunningham CL, Ryabinin AE (2011) Urocortin-1 within the centrally-projecting Edinger-Westphal nucleus is critical for ethanol preference. PLoS One 6(10):e26997. PubMedPubMedCentralCrossRefGoogle Scholar
  44. Giardino WJ, Rodriguez ED, Smith ML, Ford MM, Galili D, Mitchell SH, Chen A, Ryabinin AE (2017) Control of chronic excessive alcohol drinking by genetic manipulation of the Edinger-Westphal nucleus urocortin-1 neuropeptide system. Transl Psychiatry 7(1):e1021. PubMedPubMedCentralCrossRefGoogle Scholar
  45. Gilpin NW, Richardson HN, Koob GF (2008) Effects of CRF1-receptor and opioid-receptor antagonists on dependence-induced increases in alcohol drinking by alcohol-preferring (P) rats. Alcohol Clin Exp Res 32(9):1535–1542. PubMedPubMedCentralCrossRefGoogle Scholar
  46. Gilpin NW, Karanikas CA, Richardson HN (2012) Adolescent binge drinking leads to changes in alcohol drinking, anxiety, and amygdalar corticotropin releasing factor cells in adulthood in male rats. PLoS One 7(2):e31466. PubMedPubMedCentralCrossRefGoogle Scholar
  47. Gilpin NW, Roberto M, Koob GF, Schweitzer P (2014) Kappa opioid receptor activation decreases inhibitory transmission and antagonizes alcohol effects in rat central amygdala. Neuropharmacology 77:294–302. PubMedCrossRefGoogle Scholar
  48. Grillon C, Hale E, Lieberman L, Davis A, Pine DS, Ernst M (2015) The CRH1 antagonist GSK561679 increases human fear but not anxiety as assessed by startle. Neuropsychopharmacology 40(5):1064–1071. PubMedPubMedCentralCrossRefGoogle Scholar
  49. Haass-Koffler CL, Henry AT, Melkus G, Simms JA, Naemmuddin M, Nielsen CK, Lasek AW, Magill M, Schwandt ML, Momenan R, Hodgkinson CA, Bartlett SE, Swift RM, Bonci A, Leggio L (2016) Defining the role of corticotropin releasing factor binding protein in alcohol consumption. Transl Psychiatry 6(11):e953. PubMedPubMedCentralCrossRefGoogle Scholar
  50. Henckens MJ, Deussing JM, Chen A (2016) Region-specific roles of the corticotropin-releasing factor-urocortin system in stress. Nat Rev Neurosci 17(10):636–651. PubMedCrossRefGoogle Scholar
  51. Hershon HI (1977) Alcohol withdrawal symptoms and drinking behavior. J Stud Alcohol 38(5):953–971PubMedCrossRefGoogle Scholar
  52. Hillhouse EW, Grammatopoulos DK (2006) The molecular mechanisms underlying the regulation of the biological activity of corticotropin-releasing hormone receptors: implications for physiology and pathophysiology. Endocr Rev 27(3):260–286. PubMedCrossRefGoogle Scholar
  53. Huang MM, Overstreet DH, Knapp DJ, Angel R, Wills TA, Navarro M, Rivier J, Vale W, Breese GR (2010) Corticotropin-releasing factor (CRF) sensitization of ethanol withdrawal-induced anxiety-like behavior is brain site specific and mediated by CRF-1 receptors: relation to stress-induced sensitization. J Pharmacol Exp Ther 332(1):298–307. PubMedPubMedCentralCrossRefGoogle Scholar
  54. Hwa LS, Debold JF, Miczek KA (2013) Alcohol in excess: CRF(1) receptors in the rat and mouse VTA and DRN. Psychopharmacology 225(2):313–327. PubMedCrossRefGoogle Scholar
  55. Itoga CA, Roltsch Hellard EA, Whitaker AM, Lu YL, Schreiber AL, Baynes BB, Baiamonte BA, Richardson HN, Gilpin NW (2016) Traumatic stress promotes hyperalgesia via corticotropin-releasing factor-1 receptor (CRFR1) signaling in central amygdala. Neuropsychopharmacology 41(10):2463–2472. PubMedPubMedCentralCrossRefGoogle Scholar
  56. Jennison KM (2004) The short-term effects and unintended long-term consequences of binge drinking in college: a 10-year follow-up study. Am J Drug Alcohol Abuse 30(3):659–684PubMedCrossRefGoogle Scholar
  57. Kalin NH, Fox AS, Kovner R, Riedel MK, Fekete EM, Roseboom PH, Tromp do PM, Grabow BP, Olsen ME, Brodsky EK, McFarlin DR, Alexander AL, Emborg ME, Block WF, Fudge JL, Oler JA (2016) Overexpressing corticotropin-releasing factor in the primate amygdala increases anxious temperament and alters its neural circuit. Biol Psychiatry 80(5):345–355. PubMedPubMedCentralCrossRefGoogle Scholar
  58. Karanikas CA, Lu YL, Richardson HN (2013) Adolescent drinking targets corticotropin-releasing factor peptide-labeled cells in the central amygdala of male and female rats. Neuroscience 249:98–105. PubMedPubMedCentralCrossRefGoogle Scholar
  59. Kaur S, Li J, Stenzel-Poore MP, Ryabinin AE (2012) Corticotropin-releasing factor acting on corticotropin-releasing factor receptor type 1 is critical for binge alcohol drinking in mice. Alcohol Clin Exp Res 36(2):369–376. PubMedCrossRefGoogle Scholar
  60. Ketchesin KD, Seasholtz AF (2015) Novel roles for CRF-binding protein and CRF receptor 2 in binge drinking. Alcohol Clin Exp Res 39(12):2296–2298. PubMedPubMedCentralCrossRefGoogle Scholar
  61. Ketchesin KD, Stinnett GS, Seasholtz AF (2016) Binge drinking decreases corticotropin-releasing factor-binding protein expression in the medial prefrontal cortex of mice. Alcohol Clin Exp Res 40(8):1641–1650. PubMedPubMedCentralCrossRefGoogle Scholar
  62. Koob GF (2003) Alcoholism: allostasis and beyond. Alcohol Clin Exp Res 27(2):232–243. PubMedCrossRefGoogle Scholar
  63. Koob GF (2010) The role of CRF and CRF-related peptides in the dark side of addiction. Brain Res 1314:3–14. PubMedCrossRefGoogle Scholar
  64. Koob GF, Heinrichs SC (1999) A role for corticotropin releasing factor and urocortin in behavioral responses to stressors. Brain Res 848(1–2):141–152PubMedCrossRefGoogle Scholar
  65. Koob GF, Le Moal M (1997) Drug abuse: hedonic homeostatic dysregulation. Science 278(5335):52–58PubMedCrossRefGoogle Scholar
  66. Kwako LE, Spagnolo PA, Schwandt ML, Thorsell A, George DT, Momenan R, Rio DE, Huestis M, Anizan S, Concheiro M, Sinha R, Heilig M (2015) The corticotropin releasing hormone-1 (CRH1) receptor antagonist pexacerfont in alcohol dependence: a randomized controlled experimental medicine study. Neuropsychopharmacology 40(5):1053–1063. PubMedCrossRefGoogle Scholar
  67. Lack AK, Floyd DW, McCool BA (2005) Chronic ethanol ingestion modulates proanxiety factors expressed in rat central amygdala. Alcohol 36(2):83–90. PubMedPubMedCentralCrossRefGoogle Scholar
  68. Lai CL, Liu MT, Yin SJ, Lee JT, Lu CC, Peng GS (2012) Heavy binge drinking may increase risk of stroke in nonalcoholic hypertensives carrying variant ALDH2*2 gene allele. Acta Neurol Taiwanica 21(1):39–43Google Scholar
  69. Lam MP, Gianoulakis C (2011) Effects of acute ethanol on corticotropin-releasing hormone and beta-endorphin systems at the level of the rat central amygdala. Psychopharmacology 218(1):229–239. PubMedCrossRefGoogle Scholar
  70. 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 150(3):317–324PubMedCrossRefGoogle Scholar
  71. 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(18):7844–7849PubMedPubMedCentralCrossRefGoogle Scholar
  72. Lee S, Schmid ED, Tilders FJ, Rivier C (2001) Effect of repeated exposure to alcohol on response of hypothalamic-pituitary-adrenal axis on the rat: role of change in hypothalamic neuronal activity. Alcohol Clin Exp Res 25(1):98–105PubMedCrossRefGoogle Scholar
  73. Li Z, Kang SS, Lee S, Rivier C (2005) Effect of ethanol on the regulation of corticotropin-releasing factor (CRF) gene expression. Mol Cell Neurosci 29(3):345–354. PubMedCrossRefGoogle Scholar
  74. Liu X, Weiss F (2003) Stimulus conditioned to foot-shock stress reinstates alcohol-seeking behavior in an animal model of relapse. Psychopharmacology 168(1–2):184–191. PubMedCrossRefGoogle Scholar
  75. Lowery EG, Spanos M, Navarro M, Lyons AM, Hodge CW, Thiele TE (2010) CRF-1 antagonist and CRF-2 agonist decrease binge-like ethanol drinking in C57BL/6J mice independent of the HPA axis. Neuropsychopharmacology 35(6):1241–1252. PubMedPubMedCentralCrossRefGoogle Scholar
  76. Lowery-Gionta EG, Navarro M, Li C, Pleil KE, Rinker JA, Cox BR, Sprow GM, Kash TL, Thiele TE (2012) Corticotropin releasing factor signaling in the central amygdala is recruited during binge-like ethanol consumption in C57BL/6J mice. J Neurosci 32(10):3405–3413. PubMedPubMedCentralCrossRefGoogle Scholar
  77. Lowry CA, Moore FL (2006) Regulation of behavioral responses by corticotropin-releasing factor. Gen Comp Endocrinol 146(1):19–27. PubMedCrossRefGoogle Scholar
  78. 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 195(3):345–355. PubMedCrossRefGoogle Scholar
  79. Merchenthaler I (1984) Corticotropin releasing factor (CRF)-like immunoreactivity in the rat central nervous system. Extrahypothalamic distribution. Peptides 5(Suppl 1):53–69PubMedCrossRefGoogle Scholar
  80. 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(8):5439–5447PubMedCrossRefGoogle Scholar
  81. Mokdad AH, Marks JS, Stroup DF, Gerberding JL (2004) Actual causes of death in the United States, 2000. JAMA 291(10):1238–1245. PubMedCrossRefGoogle Scholar
  82. Morse AC, Shulteis G, Holloway FA, Koob GF (2000) Conditioned place avdersion to “hangover” phase of acute ethanol administration in the rat. Alcohol 22:19–24PubMedCrossRefGoogle Scholar
  83. Muller MB, Zimmermann S, Sillaber I, Hagemeyer TP, Deussing JM, Timpl P, Kormann MS, Droste SK, Kuhn R, Reul JM, Holsboer F, Wurst W (2003) Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress. Nat Neurosci 6(10):1100–1107. PubMedCrossRefGoogle Scholar
  84. Nie Z, Schweitzer P, Roberts AJ, Madamba SG, Moore SD, Siggins GR (2004) Ethanol augments GABAergic transmission in the central amygdala via CRF1 receptors. Science 303(5663):1512–1514. PubMedCrossRefGoogle Scholar
  85. Nie Z, Zorrilla EP, Madamba SG, Rice KC, Roberto M, Siggins GR (2009) Presynaptic CRF1 receptors mediate the ethanol enhancement of GABAergic transmission in the mouse central amygdala. ScientificWorldJournal 9:68–85. PubMedPubMedCentralCrossRefGoogle Scholar
  86. Nielsen CK, Simms JA, Li R, Mill D, Yi H, Feduccia AA, Santos N, Bartlett SE (2012) Delta-opioid receptor function in the dorsal striatum plays a role in high levels of ethanol consumption in rats. J Neurosci 32(13):4540–4552. PubMedCrossRefPubMedCentralGoogle Scholar
  87. NIH-NIAAA (2004) Alcohol facts and statistics. Accessed 5 Jan 2017
  88. Olive MF, Koenig HN, Nannini MA, Hodge CW (2002) Elevated extracellular CRF levels in the bed nucleus of the stria terminalis during ethanol withdrawal and reduction by subsequent ethanol intake. Pharmacol Biochem Behav 72(1–2):213–220PubMedCrossRefGoogle Scholar
  89. Olive MF, Mehmert KK, Koenig HN, Camarini R, Kim JA, Nannini MA, Ou CJ, Hodge CW (2003) A role for corticotropin releasing factor (CRF) in ethanol consumption, sensitivity, and reward as revealed by CRF-deficient mice. Psychopharmacology 165(2):181–187. PubMedCrossRefGoogle Scholar
  90. Overstreet DH, Knapp DJ, Breese GR (2002) Accentuated decrease in social interaction in rats subjected to repeated ethanol withdrawals. Alcohol Clin Exp Res 26(8):1259–1268. PubMedPubMedCentralCrossRefGoogle Scholar
  91. 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(2):405–413PubMedPubMedCentralCrossRefGoogle Scholar
  92. Overstreet DH, Knapp DJ, Breese GR (2007) Drug challenges reveal differences in mediation of stress facilitation of voluntary alcohol drinking and withdrawal-induced anxiety in alcohol-preferring P rats. Alcohol Clin Exp Res 31(9):1473–1481. PubMedPubMedCentralCrossRefGoogle Scholar
  93. Palmer AA, Sharpe AL, Burkhart-Kasch S, McKinnon CS, Coste SC, Stenzel-Poore MP, Phillips TJ (2004) Corticotropin-releasing factor overexpression decreases ethanol drinking and increases sensitivity to the sedative effects of ethanol. Psychopharmacology 176(3–4):386–397. PubMedCrossRefGoogle Scholar
  94. Pan W, Kastin AJ (2008) Urocortin and the brain. Prog Neurobiol 84(2):148–156. PubMedCrossRefGoogle Scholar
  95. Peng J, Long B, Yuan J, Peng X, Ni H, Li X, Gong H, Luo Q, Li A (2017) A quantitative analysis of the distribution of CRH neurons in whole mouse brain. Front Neuroanat 11:63. PubMedPubMedCentralCrossRefGoogle Scholar
  96. Phelix CF, Paull WK (1990) Demonstration of distinct corticotropin releasing factor – containing neuron populations in the bed nucleus of the stria terminalis. A light and electron microscopic immunocytochemical study in the rat. Histochemistry 94(4):345–364PubMedCrossRefGoogle Scholar
  97. Pleil KE, Rinker JA, Lowery-Gionta EG, Mazzone CM, McCall NM, Kendra AM, Olson DP, Lowell BB, Grant KA, Thiele TE, Kash TL (2015) NPY signaling inhibits extended amygdala CRF neurons to suppress binge alcohol drinking. Nat Neurosci 18(4):545–552. PubMedPubMedCentralCrossRefGoogle Scholar
  98. Pomrenze MB, Millan EZ, Hopf FW, Keiflin R, Maiya R, Blasio A, Dadgar J, Kharazia V, De Guglielmo G, Crawford E, Janak PH, George O, Rice KC, Messing RO (2015) A transgenic rat for investigating the anatomy and function of corticotrophin releasing factor circuits. Front Neurosci 9:487. PubMedPubMedCentralCrossRefGoogle Scholar
  99. Potter E, Behan DP, Linton EA, Lowry PJ, Sawchenko PE, Vale WW (1992) The central distribution of a corticotropin-releasing factor (CRF)-binding protein predicts multiple sites and modes of interaction with CRF. Proc Natl Acad Sci U S A 89(9):4192–4196PubMedPubMedCentralCrossRefGoogle Scholar
  100. Potter E, Sutton S, Donaldson C, Chen R, Perrin M, Lewis K, Sawchenko PE, Vale W (1994) Distribution of corticotropin-releasing factor receptor mRNA expression in the rat brain and pituitary. Proc Natl Acad Sci U S A 91(19):8777–8781PubMedPubMedCentralCrossRefGoogle Scholar
  101. Rasmussen DD, Boldt BM, Bryant CA, Mitton DR, Larsen SA, Wilkinson CW (2000) Chronic daily ethanol and withdrawal: 1. long-term changes in the hypothalamo-pituitary-adrenal axis. Alcohol Clin Exp Res 24(12):1836–1849Google Scholar
  102. 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(1):25–32PubMedCrossRefGoogle Scholar
  103. Redei E, Branch BJ, Gholami S, Lin EY, Taylor AN (1988) Effects of ethanol on CRF release in vitro. Endocrinology 123(6):2736–2743. PubMedCrossRefGoogle Scholar
  104. Reyes TM, Lewis K, Perrin MH, Kunitake KS, Vaughan J, Arias CA, Hogenesch JB, Gulyas J, Rivier J, Vale WW, Sawchenko PE (2001) Urocortin II: a member of the corticotropin-releasing factor (CRF) neuropeptide family that is selectively bound by type 2 CRF receptors. Proc Natl Acad Sci U S A 98(5):2843–2848. PubMedPubMedCentralCrossRefGoogle Scholar
  105. Richardson HN, Lee SY, O’Dell LE, Koob GF, Rivier CL (2008) Alcohol self-administration acute stimulates the hypothalamic-pituitary-adrenal axis, but alcohol dependence leads to a dampened neuroendocrine state. Eur J Neurosci 28(8):1641–1653PubMedPubMedCentralCrossRefGoogle Scholar
  106. Rinker JA, Marshall SA, Mazzone CM, Lowery-Gionta EG, Gulati V, Pleil KE, Kash TL, Navarro M, Thiele TE (2017) Extended amygdala to ventral tegmental area corticotropin-releasing factor circuit controls binge ethanol intake. Biol Psychiatry 81(11):930–940. PubMedCrossRefGoogle Scholar
  107. Rivier C, Lee S (1996) Acute alcohol administration stimulates the activity of hypothalamic neurons that express corticotropin-releasing factor and vasopressin. Brain Res 726(1–2):1–10PubMedCrossRefGoogle Scholar
  108. Rivier C, Vale W (1983) Modulation of stress-induced ACTH release by corticotropin-releasing factor, catecholamines and vasopressin. Nature 305(5932):325–327PubMedCrossRefGoogle Scholar
  109. Rivier C, Imaki T, Vale W (1990) Prolonged exposure to alcohol: effect on CRF mRNA levels and CRF- and stress-induced ACTH secretion in rat. Brain Res 520(1–2):1–5PubMedCrossRefGoogle Scholar
  110. Roberto M, Cruz MT, Gilpin NW, Sabino V, Schweitzer P, Bajo M, Cottone P, Madamba SG, Stouffer DG, Zorrilla EP, Koob GF, Siggins GR, Parsons LH (2010) Corticotropin releasing factor-induced amygdala gamma-aminobutyric acid release plays a key role in alcohol dependence. Biol Psychiatry 67(9):831–839. PubMedPubMedCentralCrossRefGoogle Scholar
  111. Ryabinin AE, Melia KR, Cole M, Bloom FE, Wilson MC (1995) Alcohol selectively attenuates stress-induced c-fos expression in rat hippocampus. J Neurosci 15(1 Pt 2):721–730PubMedCrossRefGoogle Scholar
  112. Ryabinin AE, Criado JR, Henriksen SJ, Bloom FE, Wilson MC (1997) Differential sensitivity of c-Fos expression in hippocampus and other brain regions to moderate and low doses of alcohol. Mol Psychiatry 2(1):32–43PubMedCrossRefGoogle Scholar
  113. Ryabinin AE, Galvan-Rosas A, Bachtell RK, Risinger FO (2003) High alcohol/sucrose consumption during dark circadian phase in C57BL/6J mice: involvement of hippocampus, lateral septum and urocortin-positive cells of the Edinger-Westphal nucleus. Psychopharmacology 165(3):296–305. PubMedCrossRefGoogle Scholar
  114. Ryabinin AE, Tsoory MM, Kozicz T, Thiele TE, Neufeld-Cohen A, Chen A, Lowery-Gionta EG, Giardino WJ, Kaur S (2012) Urocortins: CRF’s siblings and their potential role in anxiety, depression and alcohol drinking behavior. Alcohol 46(4):349–357. PubMedPubMedCentralCrossRefGoogle Scholar
  115. 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(2):175–186. PubMedCrossRefGoogle Scholar
  116. Sanchez MM, Young LJ, Plotsky PM, Insel TR (1999) Autoradiographic and in situ hybridization localization of corticotropin-releasing factor 1 and 2 receptors in nonhuman primate brain. J Comp Neurol 408(3):365–377PubMedCrossRefGoogle Scholar
  117. Sawchenko PE, Swanson LW, Vale WW (1984) Corticotropin-releasing factor: co-expression within distinct subsets of oxytocin-, vasopressin-, and neurotensin-immunoreactive neurons in the hypothalamus of the male rat. J Neurosci 4(4):1118–1129PubMedCrossRefGoogle Scholar
  118. Schreiber AL, Lu YL, Baynes BB, Richardson HN, Gilpin NW (2017) Corticotropin-releasing factor in ventromedial prefrontal cortex mediates avoidance of a traumatic stress-paired context. Neuropharmacology 113(Pt A):323–330. PubMedCrossRefGoogle Scholar
  119. Schwandt ML, Cortes CR, Kwako LE, George DT, Momenan R, Sinha R, Grigoriadis DE, Pich EM, Leggio L, Heilig M (2016) The CRF1 antagonist Verucerfont in anxious alcohol-dependent women: translation of neuroendocrine, but not of anti-craving effects. Neuropsychopharmacology 41(12):2818–2829. PubMedPubMedCentralCrossRefGoogle Scholar
  120. Sharpe AL, Coste SC, Burkhart-Kasch S, Li N, Stenzel-Poore MP, Phillips TJ (2005) Mice deficient in corticotropin-releasing factor receptor type 2 exhibit normal ethanol-associated behaviors. Alcohol Clin Exp Res 29(9):1601–1609PubMedCrossRefGoogle Scholar
  121. Shepard JD, Barron KW, Myers DA (2000) Corticosterone delivery to the amygdala increases corticotropin-releasing factor mRNA in the central amygdaloid nucleus and anxiety-like behavior. Brain Res 861(2):288–295PubMedCrossRefGoogle Scholar
  122. Shimada S, Inagaki S, Kubota Y, Ogawa N, Shibasaki T, Takagi H (1989) Coexistence of peptides (corticotropin releasing factor/neurotensin and substance P/somatostatin) in the bed nucleus of the stria terminalis and central amygdaloid nucleus of the rat. Neuroscience 30(2):377–383PubMedCrossRefGoogle Scholar
  123. Silberman Y, Matthews RT, Winder DG (2013) A corticotropin releasing factor pathway for ethanol regulation of the ventral tegmental area in the bed nucleus of the stria terminalis. J Neurosci 33(3):950–960. PubMedPubMedCentralCrossRefGoogle Scholar
  124. Simms JA, Nielsen CK, Li R, Bartlett SE (2014) Intermittent access ethanol consumption dysregulates CRF function in the hypothalamus and is attenuated by the CRF-R1 antagonist, CP-376395. Addict Biol 19(4):606–611. PubMedCrossRefGoogle Scholar
  125. Sinha R (2001) How does stress increase risk of drug abuse and relapse? Psychopharmacology 158(4):343–359. PubMedCrossRefGoogle Scholar
  126. Sommer WH, Rimondini R, Hansson AC, Hipskind PA, Gehlert DR, Barr CS, Heilig MA (2008) Upregulation of voluntary alcohol intake, behavioral sensitivity to stress, and amygdala crhr1 expression following a history of dependence. Biol Psychiatry 63(2):139–145. PubMedCrossRefGoogle Scholar
  127. Sparta DR, Sparrow AM, Lowery EG, Fee JR, Knapp DJ, Thiele TE (2008) Blockade of the corticotropin releasing factor type 1 receptor attenuates elevated ethanol drinking associated with drinking in the dark procedures. Alcohol Clin Exp Res 32(2):259–265. PubMedCrossRefGoogle Scholar
  128. Spierling SR, Zorrilla EP (2017) Don’t stress about CRF: assessing the translational failures of CRF1antagonists. Psychopharmacology 234(9–10):1467–1481. PubMedPubMedCentralCrossRefGoogle Scholar
  129. Stephens MA, Wand G (2012) Stress and the HPA axis: role of glucocorticoids in alcohol dependence. Alcohol Res 34(4):468–483PubMedPubMedCentralGoogle Scholar
  130. Suda T, Iwashita M, Tozawa F, Ushiyama T, Tomori N, Sumitomo T, Nakagami Y, Demura H, Shizume K (1988) Characterization of corticotropin-releasing hormone binding protein in human plasma by chemical cross-linking and its binding during pregnancy. J Clin Endocrinol Metab 67(6):1278–1283. PubMedCrossRefGoogle Scholar
  131. 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(2):162–166. PubMedCrossRefGoogle Scholar
  132. Turek VF, Ryabinin AE (2005) Expression of c-Fos in the mouse Edinger-Westphal nucleus following ethanol administration is not secondary to hypothermia or stress. Brain Res 1063(2):132–139. PubMedCrossRefGoogle Scholar
  133. Ungless MA, Singh V, Crowder TL, Yaka R, Ron D, Bonci A (2003) Corticotropin-releasing factor requires CRF binding protein to potentiate NMDA receptors via CRF receptor 2 in dopamine neurons. Neuron 39(3):401–407PubMedCrossRefGoogle Scholar
  134. 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 withdrawal and protracted abstinence: regulation by corticotropin-releasing factor. Alcohol Clin Exp Res 28(10):1494–1501CrossRefGoogle Scholar
  135. Valdez GF, Zorrilla EP, Roberts AJ, Koob GF (2003) Antagonism of corticotropin-releasing factor attenuates enhanced responsiveness to stress observed during protracted ethanol abstinence. Alcohol 29(2):55–60PubMedCrossRefGoogle Scholar
  136. Valdez GR, Sabino V, Koob GF (2004) Increased anxiety-like behavior and ethanol self-administration in dependent rats: reversal via corticotropin-releasing factor-2 receptor activation. Alcohol Clin Exp Res 28(6):865–872PubMedCrossRefGoogle Scholar
  137. 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(4514):1394–1397PubMedCrossRefGoogle Scholar
  138. van den Pol (2012) Neuropeptide transmission in brain circuits. Neuron 76(1):98–115PubMedPubMedCentralCrossRefGoogle Scholar
  139. Van Pett K, Viau V, Bittencourt JC, Chan RK, Li HY, Arias C, Prins GS, Perrin M, Vale W, Sawchenko PE (2000) Distribution of mRNAs encoding CRF receptors in brain and pituitary of rat and mouse. J Comp Neurol 428(2):191–212PubMedCrossRefGoogle Scholar
  140. Vendruscolo LF, Estey D, Goodell V, Macshane LG, Logrip ML, Schlosburg JE, McGinn MA, Zamora-Martinez ER, Belanoff JK, Hunt HJ, Sanna PP, George O, Koob GF, Edwards S, Mason BJ (2015) Glucocorticoid receptor antagonism decreases alcohol seeking in alcohol-dependent individuals. J Clin Invest 125(8):3193–3197. PubMedPubMedCentralCrossRefGoogle Scholar
  141. Walker LC, Kastman HE, Koeleman JA, Smith CM, Perry CJ, Krstew EV, Gundlach AL, Lawrence AJ (2016) Nucleus incertus corticotrophin-releasing factor 1 receptor signalling regulates alcohol seeking in rats. Addict Biol.
  142. Weitemier AZ, Ryabinin AE (2005) Brain region-specific regulation of urocortin 1 innervation and corticotropin-releasing factor receptor type 2 binding by ethanol exposure. Alcohol Clin Exp Res 29(9):1610–1620PubMedCrossRefGoogle Scholar
  143. Weninger SC, Peters LL, Majzoub JA (2000) Urocortin expression in the Edinger-Westphal nucleus is up-regulated by stress and corticotropin-releasing hormone deficiency. Endocrinology 141(1):256–263. PubMedCrossRefGoogle Scholar
  144. Westphal NJ, Seasholtz AF (2006) CRH-BP: the regulation and function of a phylogenetically conserved binding protein. Front Biosci 11:1878–1891PubMedCrossRefGoogle Scholar
  145. Yong W, Spence JP, Eskay R, Fitz SD, Damadzic R, Lai D, Foroud T, Carr LG, Shekhar A, Chester JA, Heilig M, Liang T (2014) Alcohol-preferring rats show decreased corticotropin-releasing hormone-2 receptor expression and differences in HPA activation compared to alcohol-nonpreferring rats. Alcohol Clin Exp Res 38(5):1275–1283. PubMedPubMedCentralCrossRefGoogle Scholar
  146. 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(3):171–181PubMedCrossRefGoogle Scholar
  147. 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(4):374–381. PubMedCrossRefGoogle Scholar
  148. 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(2):188–199PubMedCrossRefGoogle Scholar

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of PhysiologyLouisiana State University Health Science Center New OrleansNew OrleansUSA
  2. 2.Neuroscience Center of ExcellenceLouisiana State University Health Science Center New OrleansNew OrleansUSA

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