The corticotropin-releasing factor1 receptor antagonist R121919 attenuates the behavioral and endocrine responses to stress

David A. Gutman, Michael J. Owens, Kelly H. Skelton, K. V. Thrivikraman, Charles Nemeroff

Research output: Contribution to journalArticle

92 Citations (Scopus)

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 CRF1 receptor antagonist has been hypothesized to possess anxiolytic and/or antidepressant properties. In this study, an acute dose of the lipophilic CRF1 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 CRF1 receptor in the cortex measured 75-min postsubcutaneous injection. These data confirm that R121919 acts as a CRF1 receptor antagonist in vivo, attenuates HPA axis responsivity, and possesses anxiolytic properties.

Original languageEnglish
Pages (from-to)874-880
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume304
Issue number2
DOIs
StatePublished - Feb 1 2003
Externally publishedYes

Fingerprint

R 121919
Adrenocorticotropic Hormone
Corticotropin-Releasing Hormone
Anti-Anxiety Agents
Corticosterone
Hormones
Anxiety Disorders
Mood Disorders
Antidepressive Agents
Amines
Rodentia
Neck
Anxiety
Injections
CRF receptor type 1

ASJC Scopus subject areas

  • Pharmacology

Cite this

The corticotropin-releasing factor1 receptor antagonist R121919 attenuates the behavioral and endocrine responses to stress. / Gutman, David A.; Owens, Michael J.; Skelton, Kelly H.; Thrivikraman, K. V.; Nemeroff, Charles.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 304, No. 2, 01.02.2003, p. 874-880.

Research output: Contribution to journalArticle

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