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BEHAVIORAL PHARMACOLOGY

The Corticotropin-Releasing Factor₁ Receptor Antagonist R121919 Attenuates the Behavioral and Endocrine Responses to Stress

Laboratory of Neuropsychopharmacology (D.A.G., M.J.O., K.H.S., C.B.N.) and Laboratory of Stress Neurobiology (K.V.T.), Department of Psychiatry and Behavioral Sciences, Emory University of School of Medicine, Atlanta, Georgia

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.

Address correspondence to: Dr. Michael J. Owens, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 1639 Pierce Dr., Suite 4000 WMRB, Atlanta, GA 30322. E-mail: mowens{at}emory.edu

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