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Corticotropin-Releasing Factor 1 Antagonists Selectively Reduce Ethanol Self-Administration in Ethanol-Dependent Rats

      Background

      Alcohol dependence is characterized by excessive alcohol consumption, loss of control over intake, and the presence of a withdrawal syndrome, which includes both motivational and physical symptoms. Similar to human alcoholics, ethanol-dependent animals display enhanced anxiety-like behaviors and enhanced ethanol self-administration during withdrawal, effects hypothesized to result from a dysregulation of corticotropin-releasing factor (CRF) stress systems. Here, we used an animal model of ethanol dependence to test the effects of CRF1 receptor antagonists on excessive ethanol self-administration in dependent rats.

      Methods

      Wistar rats, trained to orally self-administer ethanol, were exposed intermittently to ethanol vapors to induce ethanol dependence. Nondependent animals were exposed to control air. Following a 2-hour period of withdrawal, dependent and nondependent animals were systemically administered antalarmin, MJL-1-109-2, or R121919 (CRF1 antagonists) and ethanol self-administration was measured.

      Results

      The nonpeptide, small molecule CRF1 antagonists selectively reduced excessive self-administration of ethanol in dependent animals during acute withdrawal. The antagonists had no effect on ethanol self-administration in nondependent rats.

      Conclusions

      These data demonstrate that CRF1 receptors play an important role in mediating excessive ethanol self-administration in dependent rats, with no effect in nondependent rats. CRF1 antagonists may be exciting new pharmacotherapeutic targets for the treatment of alcoholism in humans.

      Key Words

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      References

        • Alheid G.F.
        • Heimer L.
        New perspectives in basal forebrain organization of special relevance for neuropsychiatric disorders: The striatopallidal, amgdaloid, and corticopetal components of substantia innominata.
        Neuroscience. 1995; 27: 1-39
        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders. 4th ed. American Psychiatric Press, Inc, Washington, DC1994
        • Baldwin H.A.
        • Rassnick S.
        • Rivier J.
        • Koob G.F.
        CRF antagonist reverses the “anxiogenic” response to ethanol withdrawal in the rat.
        Psychopharmacology (Berl). 1991; 103: 227-232
        • Bale T.L.
        • Contarino A.
        • Smith G.W.
        • Chan R.
        • Gold L.H.
        • Sawchenko P.E.
        • et al.
        Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress.
        Nat Genet. 2000; 24: 410-414
        • Begleiter H.
        • Porjesz B.
        Persistence of a “subacute withdrawal syndrome” following chronic ethanol intake.
        Drug Alcohol Depend. 1979; 4: 353-357
        • Bloom F.E.
        • Battenberg E.L.
        • Rivier J.
        • Vale W.
        Corticotropin-releasing factor (CRF): Immunoreactive neurons and fibers in rat hypothalamus.
        Regul Pept. 1982; 4: 43-48
        • Bornstein S.R.
        • Webster E.L.
        • Torpy D.J.
        • Richman S.J.
        • Mitsiades N.
        • Igel M.
        • et al.
        Chronic effects of a nonpeptide corticotropin-releasing hormone type I-receptor antagonist on pituitary-adrenal function, and body weight and metabolic regulation.
        Endocrinology. 1998; 139: 1546-1555
        • Britton D.R.
        • Koob G.F.
        • Rivier J.
        • Vale W.
        Intraventricular corticotropin releasing factor enhances behavioral effects of novelty.
        Life Sci. 1982; 31: 363-367
        • Britton K.T.
        • Lee G.
        • Vale W.
        • Rivier J.
        • Koob G.F.
        Corticotropin releasing factor receptor (CRF) antagonist blocks activating and ’anxiogenic’ actions of CRF in the rat.
        Brain Res. 1986; 369: 303-306
        • Britton K.T.
        • Morgan J.
        • Rivier J.
        • Vale W.
        • Koob G.F.
        Chlordiazepoxide attenuates response suppression induced by corticotropin-releasing factor in the conflict test.
        Psychopharmacology (Berl). 1985; 86: 170-174
        • Chang C.P.
        • Pearse R.V.I.I.
        • O’Connell S.
        • Rosenfeld M.G.
        Identification of a seven transmembrane helix receptor for corticotropin-releasing factor and sauvagine in mammalian brain.
        Neuron. 1993; 11: 1187-1195
        • Chen C.
        • Wilcoxen K.M.
        • Huang C.Q.
        • Xie Y.F.
        • McCarthy J.R.
        • Webb T.R.
        • et al.
        Design of 2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylamino pyrazolo [1,5-a] pyrimidine (NBI 30775/R121919) and structure-activity relationships of a series of potent and orally active corticotropin-releasing factor antagonists.
        J Med Chem. 2004; 47: 4787-4798
        • Chen F.M.
        • Bilezikjian L.M.
        • Perrin M.H.
        • Rivier J.
        • Vale W.
        Corticotropin releasing factor receptor-mediated stimulation of adenylate cyclase activity in rat brain.
        Brain Res. 1986; 381: 49-57
        • Chen R.
        • Lewis K.A.
        • Perrin M.H.
        • Vale W.W.
        Expression cloning of a human corticotropin-releasing factor receptor.
        Proc Natl Acad Sci U S A. 1993; 90: 8967-8971
        • Chen Y.
        • Brunson K.L.
        • Muller M.B.
        • Cariaga W.
        • Baram T.Z.
        Immunocytochemical distribution of corticotropin-releasing hormone receptor type-1 (CRF1) -like immunoreactivity in the mouse brain: Light microscopy analysis using an antibody directed against the C-terminus.
        J Comp Neurol. 2000; 420: 305-323
        • Chen Y.L.
        Ethanol exposure decreases pituitary corticotropin-releasing factor binding, adenylate cyclase activity, proopiomelanocortin biosynthesis, and plasma beta-endorphin levels in the rat.
        Pyrrolopyrimidines as CRF antagonists. 1994
        • Dave J.R.
        • Eiden L.E.
        • Karanian J.W.
        • Eskay R.L.
        Ethanol exposure decreases pituitary corticotropin-releasing factor binding, adenylate cyclase activity, proopiomelanocortin biosynthesis, and plasma beta-endorphin levels in the rat.
        Endocrinology. 1986; 118: 280-286
        • Deak T.
        • Nguyen K.T.
        • Ehrlich A.L.
        • Watkins L.R.
        • Spencer R.L.
        • Maier S.F.
        • et al.
        The impact of the nonpeptide corticotropin-releasing hormone antagonist antalarmin on behavioral and endocrine responses to stress.
        Endocrinology. 1999; 140: 79-86
        • Dunn A.J.
        • Berridge C.W.
        Physiological and behavioral responses to corticotropin-releasing factor administration: Is CRF a mediator of anxiety or stress responses?.
        Brain Res Brain Res Rev. 1990; 15: 71-100
        • Dunn A.J.
        • File S.E.
        Corticotropin-releasing factor has an anxiogenic action in the social interaction test.
        Horm Behav. 1987; 21: 193-202
        • Ehlers C.L.
        • Chaplin R.I.
        Chronic ethanol exposure potentiates the locomotor-activating efects of corticotropin-releasing factor (CRF) in rats.
        Regul Pept. 1987; 19: 345-353
        • Ehlers C.L.
        • Chaplin R.I.
        • Wall T.L.
        • Lumeng L.
        • Li T.K.
        • Owens M.J.
        • et al.
        Corticotropin releasing factor (CRF): Studies in alcohol preferring and non-preferring rats.
        Psychopharmacology (Berl). 1992; 106: 359-364
        • File S.E.
        • Baldwin H.A.
        • Hitchcott P.K.
        Flumazenil but not nitrendipine reverses the increased anxiety during ethanol withdrawal in the rat.
        Psychopharmacology (Berl). 1989; 98: 262-264
        • Giguere V.
        • Labrie F.
        • Cote J.
        • Coy D.H.
        • Sueiras-Diaz J.
        • Schally A.V.
        Stimulation of cyclic AMP accumulation and corticotropin release by synthetic ovine corticotropin-releasing factor in rat anterior pituitary cells: Site of glucocorticoid action.
        Proc Natl Acad Sci U S A. 1982; 79: 3466-3469
        • He L.
        • Gilligan P.J.
        • Zaczek R.
        • Fitzgerald L.W.
        • McElroy J.P.
        • Shen H.S.
        • et al.
        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. 2000; 43: 449-456
        • Heinrichs S.C.
        • De Souza E.B.
        • Schulteis G.
        • Lapsansky J.L.
        • Grigoriadis D.E.
        Brain penetrance, receptor occupancy and antistress in vivo efficacy of a small molecule corticotropin releasing factor type I receptor selective antagonist.
        Neuropsychopharmacology. 2002; 27: 194-202
        • Heinrichs S.C.
        • Lapsansky J.
        • Lovenberg T.W.
        • De Souza E.B.
        • Chalmers D.T.
        Corticotropin-releasing factor CRF1, but not CRF2, receptors mediate anxiogenic-like behavior.
        Regul Pept. 1997; 71: 15-21
        • Hensler J.G.
        • Hodge C.W.
        • Overstreet D.H.
        Reduced 5-HT3 receptor binding and lower baseline plus maze anxiety in the alcohol-preferring inbred fawn-hooded rat.
        Pharmacol Biochem Behav. 2004; 77: 281-289
        • Hershon H.I.
        Alcohol withdrawal symptoms and drinking behavior.
        J Stud Alcohol. 1977; 38: 953-971
        • Hwang B.H.
        • Stewart R.
        • Zhang J.K.
        • Lumeng L.
        • Li T.K.
        Corticotropin-releasing factor gene expression is down-regulated in the central nucleus of the amygdala of alcohol-preferring rats which exhibit high anxiety: A comparison between rat lines selectively bred for high and low alcohol preference.
        Brain Res. 2004; 1026: 143-150
        • Jagoda E.
        • Contoreggi C.
        • Lee M.J.
        • Kao C.H.
        • Szajek L.P.
        • Listwak S.
        • et al.
        Autoradiographic visualization of corticotropin releasing hormone type I receptors with a nonpeptide ligand: Synthesis of [76Br]MJL-1-109-2.
        J Med Chem. 2003; 46: 3559-3562
        • Keck M.E.
        • Welt T.
        • Wigger A.
        • Renner U.
        • Engelmann M.
        • Holsboer F.
        • et al.
        The anxiolytic effect of the CRH1 receptor antagonist R121919 depends on innate emotionality in rats.
        Eur J Neurosci. 2001; 13: 373-380
        • Kishimoto T.
        • Radulovic J.
        • Radulovic M.
        • Lin C.R.
        • Schrick C.
        • Hooshmand F.
        • et al.
        Deletion of crhr2 reveals an anxiolytic role for corticotropin-releasing hormone receptor-2.
        Nat Genet. 2000; 24: 415-419
        • Kliethermes C.L.
        • Cronise K.
        • Crabbe J.C.
        Anxiety-like behavior in mice in two apparatuses during withdrawal from chronic ethanol vapor inhalation.
        Alcohol Clin Exp Res. 2004; 28: 1012-1019
        • Koob G.F.
        Neuroadaptive mechanisms of addiction: Studies on the extended amygdala.
        Eur Neuropsychopharmacol. 2003; 13: 442-452
        • Koob G.F.
        • Ahmed S.H.
        • Boutrel B.
        • Chen S.A.
        • Kenny P.J.
        • Markou A.
        • et al.
        Neurobiological mechanisms in the transition from drug use to drug dependence.
        Neurosci Biobehav Rev. 2004; 27: 739-749
        • Koob G.F.
        • Heinrichs S.C.
        A role for corticotropin releasing factor and urocortin in behavioral responses to stressors.
        Brain Res. 1999; 848: 141-152
        • Kunzel H.E.
        • Zobel A.W.
        • Nickel T.
        • Ackl N.
        • Uhr M.
        • Sonntag A.
        • et al.
        Treatment of depression with the CRH-1 receptor antagonist R121919: Endocrine changes and side effects.
        J Psychiatr Res. 2003; 37: 525-533
        • Lawrence A.J.
        • Parish C.L.
        • Chen F.
        • Lodge D.J.
        • Krstew E.V.
        • Card K.
        • et al.
        Chronic corticotropin-releasing factor type 1 receptor antagonism with antalarmin regulates the dopaminergic system of Fawn-Hooded rats.
        J Neurochem. 2005; 94: 1523-1534
        • Lee S.
        • Schmidt D.
        • Tilders F.
        • Cole M.
        • Smith A.
        • Rivier C.
        Prolonged exposure to intermittent alcohol vapors blunts hypothalamic responsiveness to immune and non-immune signals.
        Alcohol Clin Exp Res. 2000; 24: 110-122
        • Liang K.C.
        • Melia K.R.
        • Campeau S.
        • Falls W.A.
        • Miserendino M.J.D.
        • Davis M.
        Lesions of the central nucleus of the amygdala, but not the paraventricular nucleus of the hypothalamus, block the excitatory effects of corticotropin-releasing factor on the acoustic startle reflex.
        J Neurosci. 1992; 12: 2313-2320
        • Liebsch G.
        • Landgraf R.
        • Engelmann M.
        • Lorscher P.
        • Holsboer F.
        Differential behavioural effects of chronic infusion of CRH 1 and CRH 2 receptor antisense oligonucleotides into the rat brain.
        J Psychiatr Res. 1999; 33: 153-163
        • Liebsch G.
        • Landgraf R.
        • Gerstberger R.
        • Probst J.C.
        • Wotjak C.T.
        • Engelmann M.
        • et al.
        Chronic infusion of a CRH1 receptor antisense oligodeoxynucleotide into the central nucleus of the amygdala reduced anxiety-related behavior in socially defeated rats.
        Regul Pept. 1995; 59: 229-239
        • Liu J.
        • Yu B.
        • Neugebauer V.
        • Grigoriadis D.E.
        • Rivier J.
        • Vale W.W.
        • et al.
        Corticotropin-releasing factor and urocortin I modulate excitatory glutamatergic synaptic transmission.
        J Neurosci. 2004; 24: 4020-4029
        • Lodge D.J.
        • Lawrence A.J.
        The CRF1 receptor antagonist antalarmin reduces volitional ethanol consumption in isolation-reared fawn-hooded rats.
        Neuroscience. 2003; 117: 243-247
        • Lodge D.J.
        • Lawrence A.J.
        The effect of isolation rearing on volitional ethanol consumption and central CCK/dopamine systems in Fawn-Hooded rats.
        Behav Brain Res. 2003; 15: 113-122
        • Lovenberg T.W.
        • Liaw C.W.
        • Grigoriadis D.E.
        • Clevenger W.
        • Chalmers D.T.
        • De Souza E.B.
        • et al.
        Cloning and characterization of a functionally distinct corticotropin-releasing factor receptor subtype from rat brain.
        Proc Natl Acad Sci U S A. 1995; 92: 836-840
        • Macey D.J.
        • Schulteis G.
        • Heinrichs S.C.
        • Koob G.F.
        Time-dependent quantifiable withdrawal from ethanol in the rat: Effect of method of dependence induction.
        Alcohol. 1996; 13: 163-170
        • McElroy J.F.
        • Ward K.A.
        • Zeller K.L.
        • Jones K.W.
        • Gilligan P.J.
        • He L.
        • et al.
        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 (Berl). 2002; 165: 86-92
        • Menzaghi F.
        • Rassnick S.
        • Heinrichs S.
        • Baldwin H.
        • Pich E.M.
        • Weiss F.
        • et al.
        The role of corticotropin-releasing factor in the anxiogenic effects of ethanol withdrawal.
        Ann N Y Acad Sci. 1994; 739: 176-184
        • Merlo Pich E.
        • Lorang M.
        • Yeganeh M.
        • Rodriquez de Fonseca F.
        • Raber J.
        • Koob G.F.
        • et al.
        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. 1995; 15: 5439-5447
        • Muller M.B.
        • Zimmerman S.
        • Sillaber I.
        • Hagemeyer T.P.
        • Deussing J.M.
        • Timpl P.
        • et al.
        Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress.
        Nat Neurosci. 2003; 6: 1100-1107
        • National Research Council
        Guide for the Care and Use of Laboratory Animals. 7th ed. National Academy Press, Washington, DC1996
        • O’Dell L.E.
        • Roberts A.J.
        • Smith R.T.
        • Koob G.F.
        Enhanced alcohol self-administration after intermittent versus continuous alcohol vapor exposure.
        Alcohol Clin Exp Res. 2004; 28: 1676-1682
        • Olive M.F.
        • Koenig H.N.
        • Nannini M.A.
        • Hodge C.W.
        Elevated extracellular CRF levels in the bed nucleus of the stria terminalis during ethanol withdrawal and reduction by subsequent ethanol intake.
        Pharmacol Biochem Behav. 2002; 72: 213-220
        • Oshima A.
        • Flachskamm C.
        • Reul J.M.
        • Holsboer F.
        • Linthorst A.C.
        Altered serotonergic neurotransmission but normal hypothalamic-pituitary-adrenocortical axis activity in mice chronically treated with the corticotropin-releasing hormone receptor type 1 antagonist NBI 30775.
        Neuropsychopharmacology. 2003; 28: 2148-2159
        • Overstreet D.H.
        • Knapp D.J.
        • Breese G.R.
        Accentuated decrease in social interaction in rats subjected to repeated ethanol withdrawals.
        Alcohol Clin Exp Res. 2002; 26: 1259-1268
        • Overstreet D.H.
        • Knapp D.J.
        • Breese G.R.
        Modulation of multiple ethanol withdrawal-induced anxiety-like behavior by CRF and CRF1 receptors.
        Pharmacol Biochem Behav. 2004; 77: 405-413
        • Pandey S.C.
        • Roy A.
        • Zhang H.
        The decreased phosphorylation of cyclic adenosine monophosphate (cAMP) response element binding (CREB) protein in the central amygdala acts as a molecular substrate for anxiety related to ethanol withdrawal in rats.
        Alcohol Clin Exp Res. 2003; 27: 396-409
        • Pelleymounter M.A.
        • Joppa M.
        • Carmouche M.
        • Cullen M.J.
        • Brown B.
        • Murphy B.
        • et al.
        Role of corticotropin-releasing factor (CRF) receptors in the anorexic syndrome induced by CRF.
        J Pharmacol Exp Ther. 2000; 293: 799-806
        • Perrin M.H.
        • Donaldson C.J.
        • Chen R.
        • Lewis K.A.
        • Vale W.W.
        Cloning and functional expression of a rat brain corticotropin releasing factor (CRF) receptor.
        Endocrinology. 1993; 133: 3058-3061
        • Rassnick S.
        • Heinrichs S.C.
        • Britton K.T.
        • Koob G.F.
        Microinjection of a corticotropin-releasing factor antagonist into the central nucleus of the amygdala reverses anxiogenic-like effects of ethanol withdrawal.
        Brain Res. 1993; 605: 25-32
        • Rivier C.
        • Bruhn T.
        • Vale W.
        Effect of ethanol on the hypothalamic-pituitary-adrenal axis in the rat: Role of corticotropin-releasing factor (CRF).
        J Pharmacol Exp Ther. 1984; 229: 127-131
        • Rivier C.
        • Imaki T.
        • Vale W.
        Prolonged exposure to alcohol: Effect on CRF mRNA levels, and CRF and stress-induced ACTH secretion in the rat.
        Brain Res. 1990; 520: 1-5
        • Rivier C.
        • Rivier J.
        • Vale W.
        Inhibition of adrenocorticotropic hormone secretion in the rat by immunoneutralization of corticotropin-releasing factor.
        Science. 1982; 218: 377-379
        • Roberto M.
        • Madamba S.G.
        • Stouffer D.G.
        • Parsons L.H.
        • Siggins G.R.
        Increased GABA release in the central amygdala of ethanol-dependent rats.
        J Neurosci. 2004; 24: 10159-10166
        • Roberts A.J.
        • Heyser C.J.
        • Cole M.
        • Griffin P.
        • Koob G.F.
        Excessive ethanol drinking following a history of dependence: Animal model of allostasis.
        Neuropsychopharmacology. 2000; 22: 581-594
        • Roberts A.J.
        • Heyser C.J.
        • Koob G.F.
        Operant self-administration of sweetened versus unsweetened ethanol: Effects on blood alcohol levels.
        Alcohol Clin Exp Res. 1999; 23: 1151-1157
        • Roozendaal B.
        • Brunson K.L.
        • Holloway B.L.
        • McGaugh J.L.
        • Baram T.Z.
        Involvement of stress-released corticotropin-releasing hormone in the basolateral amygdala in regulating memory consolidation.
        Proc Natl Acad Sci U S A. 2002; 99: 13908-13913
        • Samson H.H.
        Initiation of ethanol reinforcement using a sucrose-substitution procedure in food- and water-sated rats.
        Alcohol Clin Exp Res. 1986; 10: 436-442
        • Slawecki C.J.
        • Somes C.
        • Ehlers C.L.
        Effects of chronic ethanol exposure on neurophysiological responses to corticotropin-releasing factor and neuropeptide Y.
        Alcohol Alcohol. 1999; 34: 289-299
        • Smith G.W.
        • Aubry J.M.
        • Dellu F.
        • Contarino A.
        • Bilezikjiam L.M.
        • Gold L.H.
        • et al.
        Corticotropin-releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development.
        Neuron. 1998; 20: 1093-1102
        • Spina M.
        • Merlo-Pich E.
        • Chan R.K.W.
        • Basso A.M.
        • Rivier J.
        • Vale W.
        • et al.
        Appetite-suppressing effects of urocortin, a CRF-related neuropeptide.
        Science. 1996; 273: 1561-1564
        • Stinson F.S.
        • Dufour M.C.
        • Steffens R.A.
        • DeBakey S.F.
        Alcohol-related mortality in the United States, 1979–1989.
        Alcohol Health Res World. 1993; 17: 251-260
        • Stinus L.
        • Cador M.
        • Zorrilla E.P.
        • Koob G.F.
        Buprenorphine and a CRF1 antagonist block the acquisition of opiate withdrawal-induced conditioned place preference.
        Neuropsychopharmacology. 2005; 30: 90-98
        • Sutton R.E.
        • Koob G.F.
        • Le Moal M.
        • Rivier J.
        • Vale W.
        Corticotropin releasing factor produces behavioural activation in rats.
        Nature. 1982; 297: 331-333
        • Swerdlow N.R.
        • Britton K.T.
        • Koob G.F.
        Potentiation of acoustic startle by corticotropin-releasing factor (CRF) and by fear are both reversed by alpha-helical CRF (9–41).
        Neuropsychopharmacology. 1989; 2: 285-292
        • Swerdlow N.R.
        • Geyer M.A.
        • Vale W.W.
        • Koob G.F.
        Corticotropin-releasing factor potentiates acoustic startle in rats: Blockade by chlordiazepoxide.
        Psychopharmacology (Berl). 1986; 88: 147-152
        • Timpl P.
        • Spanagel R.
        • Sillaber I.
        • Kresse A.
        • Reul J.M.H.M.
        • Stalla G.K.
        • et al.
        Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1.
        Nat Genet. 1998; 19: 162-166
        • Valdez G.R.
        • Inoue K.
        • Koob G.F.
        • Rivier J.
        • Vale W.
        • Zorrilla E.P.
        Human urocortin II: Mild locomotor suppressive and delayed anxiolytic-like effects of a novel corticotropin-releasing factor related peptide.
        Brain Res. 2002; 943: 142-150
        • Valdez G.R.
        • Koob G.F.
        Allostasis and dysregulation of corticotropin-releasing factor and neuropeptide Y systems: Implications for the development of alcoholism.
        Pharmacol Biochem Behav. 2004; 79: 671-689
        • Valdez G.R.
        • Roberts A.J.
        • Chan K.
        • Davis H.
        • Brennan M.
        • Zorrilla E.P.
        • et al.
        Increased ethanol self-administration and anxiety-like behavior during acute ethanol withdrawal and protracted abstinence: Regulation by corticotropin-releasing factor.
        Alcohol Clin Exp Res. 2002; 26: 1494-1501
        • Valdez G.R.
        • Zorrilla E.P.
        • Rivier J.
        • Vale W.W.
        • Koob G.F.
        Locomotor suppressive and anxiolytic-like effects of urocortin 3, a highly selective type 2 corticotropin-releasing factor agonist.
        Brain Res. 2003; 980: 206-212
        • Valdez G.R.
        • Zorrilla E.P.
        • Roberts A.J.
        • Koob G.F.
        Antagonism of corticotropin-releasing factor attenuates the enhanced responsiveness to stress observed during protracted ethanol abstinence.
        Alcohol. 2003; 29: 55-60
        • Vale W.
        • Rivier C.
        • Brown M.R.
        • Spiess J.
        • Koob G.
        • Swanson L.
        • et al.
        Chemical and biological characterization of corticotropin releasing factor.
        Recent Prog Horm Res. 1983; 39: 245-270
        • Vale W.
        • Spiess J.
        • Rivier C.
        • Rivier J.
        Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin.
        Science. 1981; 213: 1394-1397
        • Van Pett K.
        • Viau V.
        • Bittencourt J.C.
        • Chan R.K.W.
        • Li H.Y.
        • Arias C.
        • et al.
        Distribution of mRNAs encoding CRF receptors in brain and pituitary of rat and mouse.
        J Comp Neurol. 2000; 428: 191-212
        • Walker D.L.
        • Davis M.
        Double dissociation between the involvement of the bed nucleus of the stria terminalis and the central nucleus of the amygdala in startle increases produced by conditioned versus unconditioned fear.
        J Neurosci. 1997; 17: 9375-9383
        • Webster E.L.
        • Lewis D.B.
        • Torpy D.J.
        • Zachman E.K.
        • Rice K.C.
        • Chrousos G.P.
        In vivo and in vitro characterization of antalarmin, a nonpeptide corticotropin-releasing hormone (CRH) receptor antagonist: Suppression of pituitary ACTH release and peripheral inflammation.
        Endocrinology. 1996; 137: 5747-5750
        • Wong M.L.
        • Webster E.L.
        • Spokes H.
        • Phu P.
        • Ehrhart-Bornstein M.
        • Bornstein S.
        • et al.
        Chronic administration of the non-peptide CRH type 1 receptor antagonist antalarmin does not blunt hypothalamic-pituitary-adrenal axis response to acute immobilization stress.
        Life Sci. 1999; 65: PL53-PL58
        • Yoshimoto K.
        • Ueda S.
        • Kato B.
        • Takeuchi Y.
        • Kawai Y.
        • Noritake K.
        • et al.
        Alcohol enhances characteristic releases of dopamine and serotonin in the central nucleus of the amygdala.
        Neurochem Int. 2000; 37: 369-376
        • Yu-Wen L.
        • Hill G.
        • Wong H.
        • Kelly N.
        • Ward K.
        • Pierdomenico M.
        • et al.
        Receptor occupancy of nonpeptide corticotropin-releasing factor 1 antagonist DMP696: Correlation with drug exposure and anxiolytic efficacy.
        J Pharmacol Exp Ther. 2003; 305: 86-96
        • Zobel A.W.
        • Nickel T.
        • Kunzel H.E.
        • Ackl N.
        • Sonntag A.
        • Ising M.
        • et al.
        Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: The first 20 patients treated.
        J Psychiatr Res. 2000; 34: 171-181
        • Zorrilla E.P.
        • Koob G.F.
        The therapeutic potential of CRF1 antagonists for anxiety.
        Expert Opin Investig Drugs. 2004; 13: 799-828
        • Zorrilla E.P.
        • Valdez G.R.
        • Nozulak J.
        • Koob G.F.
        • Markou A.
        Effects of antalarmin, a CRF type 1 receptor antagonist, on anxiety-like behavior and motor activation in the rat.
        Brain Res. 2002; 952: 188-199
        • Zorrilla E.P.
        • Valdez G.R.
        • Weiss F.
        Changes in levels of regional CRF-like immunoreactivity and plasma corticosterone during protracted drug withdrawal in dependent rats.
        Psychopharmacology (Berl). 2001; 158: 374-381