title: Identification of molecules potentially involved in mediating the in vivo actions of the corticotropin-releasing hormone receptor 1 antagonist, NBI30775 (R121919).
abstract: BACKGROUND
  The neuropeptide corticotropin-releasing hormone (CRH) plays a central role in the regulation of the hypothalamo-pituitary-adrenocortical (HPA) axis. The view that CRH hypersecretion underlies anxiety and mood disorders was recently supported by preclinical and clinical data obtained after application of the CRH receptor (CRH-R1) antagonist NBI30775 (R121919). Despite its therapeutic efficacy, there is only little information about its mechanisms of action on cellular and molecular targets.
  
  
  OBJECTIVE
  To identify some of the intracellular substrates mediating the actions of NBI30775 after its acute administration in a stress-independent animal model.
  
  
  RESULTS
  Of the different doses of NBI30775 tested (0.5, 1, 5 and 30 mg/kg), the 1-mg/kg dose proved behaviorally active insofar that it reduced anxiety-like behavior in mice under basal conditions. Subsequent analysis of brain tissues revealed NBI30775-induced increases in the nuclear translocation of glucocorticoid receptors (GR) and BAG-1, an upregulation of mRNA transcripts encoding GR, mineralocorticoid receptors (MR) and CRH-R1, and a suppression of the DNA-binding activity of the transcription factor AP-1. These changes were significant at a dose of 1 mg/kg of NBI30775.
  
  
  CONCLUSIONS
  NBI30775 reduces levels of anxiety in mice (under basal conditions) with a steep dose-response curve. Molecules such as GR, MR, BAG-1 and AP-1 have been identified as some of the drug's intracellular targets; interestingly, changes in these molecules have also been seen in response to conventional antidepressants, showing that structurally and mechanistically unrelated anxiolytic and antidepressant drugs can influence common downstream pathways.
authors.affiliation: Max Planck Institute of Psychiatry, Kraepelinstrasse 10, 80804 Munich, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Post
authors.forename: Frauke
authors.initials: F
authors.lastname: Ohl
authors.forename: Osborne F X
authors.initials: OF
authors.lastname: Almeida
authors.forename: Elisabeth B
authors.initials: EB
authors.lastname: Binder
authors.forename: Monika
authors.initials: M
authors.lastname: Rücker
authors.forename: Sandra
authors.initials: S
authors.lastname: Welt
authors.forename: Elke
authors.initials: E
authors.lastname: Binder
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.forename: Inge
authors.initials: I
authors.lastname: Sillaber
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis / Q000235:genetics; D018161:Receptors, Mineralocorticoid / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018808:Transcription Factor AP-1 / Q000096:biosynthesis / Q000235:genetics; D015533:Transcriptional Activation; D015854:Up-Regulation; D000099052:CRF Receptor, Type 1
chemical_list: D014151:Anti-Anxiety Agents; D016328:NF-kappa B; D011743:Pyrimidines; C412383:R 121919; D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D018808:Transcription Factor AP-1; D000099052:CRF Receptor, Type 1; D003345:Corticosterone