Stress and central Urocortin increase anxiety-like behavior in the social interaction test via the CRF1 receptor.
Corticotropin releasing factor (CRF) and Urocortin are important neurotransmitters in the regulation of physiological and behavioral responses to stress. Centrally administered CRF or Urocortin produces anxiety-like responses in numerous animal models of anxiety disorders. Previous studies in our lab have shown that Urocortin infused into the basolateral nucleus of the amygdala produces anxiety-like responses in the social interaction test. Subsequently, in the current study we prepared a specific CRF1 receptor antagonist (N-Cyclopropylmethyl-2,5-dimethyl-N-propyl-N'-(2,4,6-trichloro-phenyl)-pyrimidine-4,6-diamine, NBI3b1996) to examine in this paradigm. This CRF1 receptor antagonist inhibited the ex vivo binding of 125I-sauvagine to rat cerebellum with an ED50 of 6 mg/kg, i.p. NBI3b1996 produced a dose-dependent antagonism of Urocortin-induced anxiety-like behavior in Social Interaction test with an ED50 of 6 mg/kg, i.p. The compound had no effect on baseline social interaction. In addition, the CRF1 receptor antagonist prevented the stress-induced decrease in social interaction. These results provide further support for the CRF1 receptor in anxiety-like behavior and suggest this pathway is quiescent in unstressed animals.
Gehlert
Donald R
DR
Neuroscience Division DC0510, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285-0510, United States. gehlert_donald_r@lilly.com
Shekhar
Anantha
A
Morin
S Michelle
SM
Hipskind
Phillip A
PA
Zink
Charity
C
Gackenheimer
Susan L
SL
Shaw
Janice
J
Fitz
Stephanie D
SD
Sajdyk
Tammy J
TJ
D029845:Amphibian Proteins; D000818:Animals; D001008:Anxiety Disorders / Q000209:etiology / Q000503:physiopathology*; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007457:Iodine Radioisotopes; D008297:Male; D036361:Peptide Hormones; D010455:Peptides / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012149:Restraint, Physical; D012919:Social Behavior; D013315:Stress, Psychological / Q000503:physiopathology*; D054832:Urocortins; D000099052:CRF Receptor, Type 1
D029845:Amphibian Proteins; D007457:Iodine Radioisotopes; C501105:N-cyclopropylmethyl-2,5-dimethyl-N-propyl-N'-(2,4,6-trichloro-phenyl)-pyrimidine-4,6-diamine; D036361:Peptide Hormones; D010455:Peptides; D011743:Pyrimidines; D018019:Receptors, Corticotropin-Releasing Hormone; D054832:Urocortins; D000099052:CRF Receptor, Type 1; C025727:sauvagine; D003346:Corticotropin-Releasing Hormone