title: Stress and central Urocortin increase anxiety-like behavior in the social interaction test via the CRF1 receptor.
abstract: 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.
authors.affiliation: Neuroscience Division DC0510, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285-0510, United States. gehlert_donald_r@lilly.com
authors.forename: Donald R
authors.initials: DR
authors.lastname: Gehlert
authors.forename: Anantha
authors.initials: A
authors.lastname: Shekhar
authors.forename: S Michelle
authors.initials: SM
authors.lastname: Morin
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Hipskind
authors.forename: Charity
authors.initials: C
authors.lastname: Zink
authors.forename: Susan L
authors.initials: SL
authors.lastname: Gackenheimer
authors.forename: Janice
authors.initials: J
authors.lastname: Shaw
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Fitz
authors.forename: Tammy J
authors.initials: TJ
authors.lastname: Sajdyk
mesh_terms: 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
chemical_list: 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