Persistent anxiolytic affects after chronic administration of the CRF₁ receptor antagonist R121919 in rats

Abstract

Corticotropin-releasing factor (CRF) functions as one of the major mediators of the mammalian stress response and appears to play a key role in the pathophysiology of mood and anxiety disorders. Small molecule CRF₁ receptor antagonists may represent a novel form of pharmacotherapy for these disorders. The therapeutic success of CRF₁ receptor antagonists will depend, in part, upon whether tolerance develops to the actions of these compounds and whether appropriate patterns of HPA axis function is maintained. This study evaluated the effects of long term (~4 week) treatment with the CRF₁ receptor antagonist R121919, on CRF receptor function, HPA axis activity, behavioral measures, adrenal gland size, and body weight gain. Animals treated with 20 mg/kg/day of R121919 spent significantly more time in the open field in a defensive withdrawal test (138±36s for R121919 vs 52±12s for vehicle, p=0.01). No significant effect of chronic CRF₁ receptor blockade on basal ACTH or corticosterone concentrations were detected, nor were significant changes detected in an elevated plus maze test. Both vehicle- and R121919- treated rats showed increases in AUC and peak ACTH and corticosterone concentrations following air puff startle stress, without any overall group differences, although a clear but non-significant attenuation in HPA axis response was observable in R121919 treated animals. Chronic CRF₁ receptor blockade increased CRF peptide mRNA expression in the PVN and decreased CRF peptide mRNA expression in the central nucleus of the amygdala. Overall our results suggest that anxiolytic effects of chronic CRF₁ receptor antagonism persist following chronic administration without significant attenuation of the HPA axis's ability to mount a stress response. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.

Figure 1

Basal and Stimulated Endocrine Values after Defensive Withdrawal. There were no significant changes in either basal or stimulated endocrine values after a defensive withdrawal in animals treated with R121919 (20 mg/kg/day) for 30 days.

Figure 2

ACTH and corticosterone response to an air puff startle following 25 days of R121919 (20 mg/kg/day) treatment.

Figure 3

[A] Total time spent out of the tube during a 15 minute defensive withdrawal. Chronic R121919 (20 mg/kg/day) administration significantly increased the total time spent in the arena (p=0.016). [B] R121919 did not significantly attenuate the latency to enter the arena (p=0.108) s=seconds

Figure 4

Representative in situ hybridization images showing an increased (upper left image) density of CRF mRNA in the PVN (left,top) following chronic administration of R121919 and decreased CRF mRNA in the central nucleus of the amygdala (CeA) (right, top image)