The anxiolytic effect of the CRH(1) receptor antagonist R121919 depends on innate emotionality in rats.
Hyperactivity of central corticotropin-releasing hormone (CRH) circuits appears to contribute to the symptomatology of affective and anxiety disorders and therefore CRH receptor antagonists have attracted attention as potential therapeutic agents. R121919, a novel high-affinity nonpeptide CRH(1) receptor antagonist, displaced (125)I-oCRH in rat pituitary, cortex and amygdala, but not in choroid plexus or cerebral blood vessels in vitro and in vivo, which is consistent with CRH(1) receptor antagonism. In vivo, R121919 significantly inhibited stress-induced corticotropin release in rats selectively bred for high- and low-anxiety-related behaviour but displayed anxiolytic effects in high-anxiety rats only. These data, corroborated by ex vivo receptor occupancy studies, suggest that this animal model is appropriate for the evaluation of CRH(1) receptor antagonists and that compounds such as R121919 will be beneficial whenever the central stress hormone system is hyperactive.
Keck
M E
ME
Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, D-80804 Munich, Germany. keck@mpipsykl.mpg.de
Welt
T
T
Wigger
A
A
Renner
U
U
Engelmann
M
M
Holsboer
F
F
Landgraf
R
R
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy*; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001923:Brain Chemistry / Q000187:drug effects; D001947:Breeding; D002478:Cells, Cultured; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D006948:Hyperkinesis / Q000188:drug therapy; D007457:Iodine Radioisotopes; D008297:Male; D009474:Neurons / Q000737:chemistry / Q000378:metabolism; D010904:Pituitary Gland, Posterior / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D018019:Receptors, Corticotropin-Releasing Hormone / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014162:Transfection
D014151:Anti-Anxiety Agents; D007457:Iodine Radioisotopes; D011743:Pyrimidines; C412383:R 121919; D018019:Receptors, Corticotropin-Releasing Hormone; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone