Identification of molecules potentially involved in mediating the in vivo actions of the corticotropin-releasing hormone receptor 1 antagonist, NBI30775 (R121919).
Psychopharmacology (Berl)
; 180(1): 150-8, 2005 Jun.
Article
em En
| MEDLINE
| ID: mdl-15682302
ABSTRACT
RATIONALE 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.CONCLUSION:
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
/
Ansiolíticos
/
Receptores de Hormônio Liberador da Corticotropina
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2005
Tipo de documento:
Article