title: The corticotropin-releasing factor1 receptor antagonist R121919 attenuates the behavioral and endocrine responses to stress.
abstract: Corticotropin-releasing factor (CRF) is the major physiological regulator of the hypothalamic-pituitary-adrenal (HPA) axis and serves to coordinate the mammalian endocrine, autonomic, and behavioral responses to stress. Considerable literature from clinical and preclinical data suggests that hypersecretion of hypothalamic and/or extrahypothalamic CRF systems is a major factor in the pathogenesis of affective and anxiety disorders. Based on this premise, a CRF(1) receptor antagonist has been hypothesized to possess anxiolytic and/or antidepressant properties. In this study, an acute dose of the lipophilic CRF(1) receptor antagonist 3-[6-(dimethylamino)-4-methyl-pyrid-3-yl]-2,5-dimethyl-N,N-dipropyl-pyrazolo[2,3-a]pyrimidin-7-amine (R121919), administered i.v. to rats with surgically implanted jugular cannula 60 min before a 5-min restraint stress, dose dependently attenuated peak plasma adrenocorticopin hormone (ACTH) and corticosterone concentrations by 91 and 75%, respectively. In a second study, acute administration of R121919 reduced measures of anxiety in a rodent defensive withdrawal paradigm. R121919 dose dependently decreased latency to exit the tube, and total time spent in the tube 60 min after a single subcutaneous administration. In addition, the ACTH and corticosterone response to novelty was decreased by 82 and 97%, respectively, at the 10-mg/kg dose of R121919. In another study, this dose was associated with approximately an 85% occupancy of the CRF(1) receptor in the cortex measured 75-min postsubcutaneous injection. These data confirm that R121919 acts as a CRF(1) receptor antagonist in vivo, attenuates HPA axis responsivity, and possesses anxiolytic properties.
authors.affiliation: Laboratory of Neuropsychopharmacology, Department of Psychiatry and Behavioral Sciences, Emory University of School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Gutman
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owens
authors.forename: Kelly H
authors.initials: KH
authors.lastname: Skelton
authors.forename: K V
authors.initials: KV
authors.lastname: Thrivikraman
authors.forename: Charles B
authors.initials: CB
authors.lastname: Nemeroff
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology / Q000627:therapeutic use; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D003345:Corticosterone / Q000097:blood; D004703:Endocrine System / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013312:Stress, Physiological / Q000097:blood* / Q000188:drug therapy / Q000523:psychology; D000099052:CRF Receptor, Type 1
chemical_list: D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D011743:Pyrimidines; C412383:R 121919; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone