title: Impaired emotional learning and involvement of the corticotropin-releasing factor signaling system in patients with irritable bowel syndrome.
abstract: OBJECTIVE
  Alterations in central corticotropin-releasing factor signaling pathways have been implicated in the pathophysiology of anxiety disorders and irritable bowel syndrome (IBS). We aimed to characterize the effects of the corticotropin-releasing factor receptor 1 (CRF-R1) antagonist, GW876008, on brain and skin conductance responses during acquisition and extinction of conditioned fear to the threat of abdominal pain in subjects with IBS and healthy individuals (controls).
  
  
  METHODS
  We performed a single-center, randomized, double-blind, 3-period crossover study of 11 women with IBS (35.50 ± 12.48 years old) and 15 healthy women (controls) given a single oral dose (20 mg or 200 mg) of the CRF-R1 antagonist or placebo. Blood-oxygen level-dependent responses were analyzed using functional magnetic resonance imaging in a tertiary care setting.
  
  
  RESULTS
  Controls had greater skin conductance responses during acquisition than extinction, validating the fear-conditioning paradigm. In contrast, during extinction, women with IBS had greater skin conductance responses than controls-an effect normalized by administration of a CRF-R1 antagonist. Although the antagonist significantly reduced activity in the thalamus in patients with IBS and controls during acquisition, the drug produced greater suppression of blood-oxygen level-dependent activity in a wide range of brain regions in IBS patients during extinction, including the medial prefrontal cortex, pons, hippocampus, and anterior insula.
  
  
  CONCLUSIONS
  Although CRF signaling via CRF-R1 is involved in fear acquisition and extinction learning related to expected abdominal pain in patients with IBS and controls, this system appears to be up-regulated in patients with IBS. This up-regulation might contribute to the previously reported abnormal brain responses to expected abdominal pain.
authors: Gail and Gerald Oppenheimer Family Center for the Neurobiology of Stress, University of California, Los Angeles, Los Angeles, California; Department of Medicine, University of California, Los Angeles, Los Angeles, California; Department of Psychiatry, University of California, Los Angeles, Los Angeles, California.
authors: Jennifer S
authors: JS
authors: Labus
authors: Catherine S
authors: CS
authors: Hubbard
authors: Joshua
authors: J
authors: Bueller
authors: Bahar
authors: B
authors: Ebrat
authors: Kirsten
authors: K
authors: Tillisch
authors: Michelle
authors: M
authors: Chen
authors: Jean
authors: J
authors: Stains
authors: George E
authors: GE
authors: Dukes
authors: Dennis L
authors: DL
authors: Kelleher
authors: Bruce D
authors: BD
authors: Naliboff
authors: Michael
authors: M
authors: Fanselow
authors: Emeran A
authors: EA
authors: Mayer
mesh_terms: D015746:Abdominal Pain / Q000503:physiopathology / Q000523:psychology; D000328:Adult; D001008:Anxiety Disorders / Q000503:physiopathology* / Q000523:psychology; D001921:Brain / Q000502:physiology; D001931:Brain Mapping; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000502:physiology*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005108:Extinction, Psychological / Q000502:physiology*; D005239:Fear / Q000502:physiology / Q000523:psychology; D005260:Female; D005712:Galvanic Skin Response / Q000187:drug effects / Q000502:physiology; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000503:physiopathology*; D008875:Middle Aged; D011720:Pyrazoles / Q000494:pharmacology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000099052:CRF Receptor, Type 1
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; C552097:GW 876008; D011720:Pyrazoles; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone
keywords: AMYG; BOLD; CRF-R1; Corticotropin-Releasing Factor Receptor 1 (CRF-R1) Antagonist; Extinction; Fear Conditioning; HCs; HIPP; HYPO; IBS; LCC; PLA; SCR; SNS; THAL; aINS; aMCC; amygdala; anterior insula; anterior midcingulate cortex; blood-oxygen level−dependent; corticotropin-releasing factor receptor 1; dlPFC; dorsolateral prefrontal cortex; healthy controls; hippocampus; hypothalamus; irritable bowel syndrome; locus coeruleus complex; mPFC; medial prefrontal cortex; pACC; placebo; pregenual anterior cingulate cortex; skin conductance responses; sympathetic nervous system; thalamus; ventrolateral prefrontal cortex; vlPFC
references: Biol Psychiatry. 2004 Feb 15;55(4):359-66
references: 14960288
references: Annu Rev Psychol. 2012;63:129-51
references: 22129456
references: Science. 2000 Jun 9;288(5472):1835-8
references: 10846167
references: Biol Psychiatry. 2006 Aug 15;60(4):383-7
references: 16780813
references: Curr Opin Neurobiol. 2000 Apr;10(2):219-23
references: 10753800
references: Proc Natl Acad Sci U S A. 1986 Mar;83(6):1921-5
references: 2869491
references: Brain Res. 1977 May 20;127(1):1-21
references: 67877
references: J Neurosci. 1999 Dec 15;19(24):10869-76
references: 10594068
references: Trends Cogn Sci. 2003 Sep;7(9):415-423
references: 12963473
references: J Clin Psychiatry. 1996 Dec;57(12):576-8
references: 9010120
references: Am J Physiol Gastrointest Liver Physiol. 2001 Apr;280(4):G519-24
references: 11254476
references: Am J Psychiatry. 1999 Nov;156(11):1787-95
references: 10553744
references: J Comp Neurol. 1999 Jun 7;408(3):365-77
references: 10340512
references: Brain Res Brain Res Rev. 1990 May-Aug;15(2):71-100
references: 1980834
references: J Gastroenterol. 2007 Jan;42 Suppl 17:48-51
references: 17238026
references: J Neurosci. 2008 Jan 9;28(2):349-59
references: 18184777
references: Neurology. 2008 Jan 8;70(2):153-4
references: 17959767
references: J Clin Psychiatry. 1998;59 Suppl 20:22-33;quiz 34-57
references: 9881538
references: Neurosci Biobehav Rev. 2003 Oct;27(6):555-79
references: 14599436
references: PLoS One. 2009 Jun 10;4(6):e5865
references: 19517024
references: Semin Clin Neuropsychiatry. 2001 Apr;6(2):102-12
references: 11296310
references: Neuropsychopharmacology. 2008 Jan;33(1):56-72
references: 17882236
references: Gastroenterology. 2012 Mar;142(3):463-472.e3
references: 22108191
references: CNS Spectr. 2009 Jan;14(1 Suppl 1):13-24
references: 19169190
references: Eur J Intern Med. 2006 Dec;17(8):567-71
references: 17142176
references: Psychosom Med. 2008 Oct;70(8):920-7
references: 18842745
references: J Neurosci. 2011 Aug 31;31(35):12491-500
references: 21880911
references: Biol Psychiatry. 2006 Aug 15;60(4):376-82
references: 16919525
references: Pharmacol Ther. 2010 Dec;128(3):460-87
references: 20826181
references: Behav Pharmacol. 1997 Nov;8(6-7):477-96; discussion 497-504
references: 9832964
references: Biol Psychol. 2006 Jul;73(1):39-48
references: 16472906
references: Curr Gastroenterol Rep. 2009 Aug;11(4):270-7
references: 19615302
references: J Comp Neurol. 2000 Dec 11;428(2):191-212
references: 11064361
references: Gastroenterology. 2006 Apr;130(5):1480-91
references: 16678561
references: CNS Spectr. 2008 Jun;13(6):467-83
references: 18567971
references: Neuron. 2004 Sep 16;43(6):897-905
references: 15363399
references: Behav Res Ther. 2006 May;44(5):621-38
references: 16039604
references: Neuropsychopharmacology. 2010 Jan;35(1):169-91
references: 19625997
references: Biol Psychiatry. 2007 Sep 1;62(5):446-54
references: 17217927
references: Gastroenterology. 2010 Oct;139(4):1310-9
references: 20600024
references: Neuroscience. 1986 Jun;18(2):291-306
references: 3736860
references: Gastroenterology. 2005 Jun;128(7):1819-29
references: 15940617
references: Neuron. 2008 Sep 11;59(5):829-38
references: 18786365
references: Biol Psychol. 2010 May;84(2):272-8
references: 20193731
references: J Med Chem. 2008 Dec 11;51(23):7370-9
references: 18989952
references: J Comp Neurol. 1982 Mar 1;205(3):260-72
references: 6122696
references: Arch Intern Med. 2004 Sep 13;164(16):1773-80
references: 15364671
references: Aliment Pharmacol Ther. 2013 Feb;37(3):304-15
references: 23205588
references: Cereb Cortex. 2010 Apr;20(4):929-40
references: 19679543
references: Science. 1981 Sep 18;213(4514):1394-7
references: 6267699
references: Dig Dis Sci. 2008 Jun;53(6):1652-9
references: 17990112