The Corticotropin-Releasing Factor₁Receptor 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.

Altered Serotonergic Neurotransmission but Normal Hypothalamic–Pituitary–Adrenocortical Axis Activity in Mice Chronically Treated with the Corticotropin-Releasing Hormone Receptor Type 1 Antagonist NBI 30775

“…The reasons for the absence of antidepressant properties of NBI 30775 in our study are not clear. A very low dose of the drug is not likely to be the cause, because the dose used in this study, as well as lower doses, have been reported to exert anxiolytic effects in various tests in rats (Keck et al, 2001;Heinrichs et al, 2002;Gutman et al, 2003). Moreover, as indicated by the changes in serotonergic neurotransmission reported here, NBI 30775 shows biological activity not only in rats but also in mice.…”

“…However, treatment regimens in which drugs have been added to the drinking water or food have successfully been used to demonstrate the effects of various antidepressants on HPA axis regulation (see Reul et al, 1993Reul et al, , 1994Bachmann et al, 2003). Although we did not study receptor occupation after chronic treatment with NBI 30775, a recent report by Gutman et al (2003) shows that even 8 h after acute intravenous administration of NBI 30775 (10 mg/kg body weight), 45% of CRH-R1 in the rat frontal cortex are still occupied by the antagonist. Moreover, binding of NBI 30775 to CRH-R1 was found to be dose-dependent.…”

“…Whereas CRH-R1 antagonists blunt stress-induced increases in plasma ACTH and corticosterone after acute administration (Arborelius et al, 2000;Keck et al, 2001;Heinrichs et al, 2002;Gutman et al, 2003), chronic oral treatment with NBI 30775 had no consequences for HPA axis functioning. As compared to the control group, NBI 30775-treated mice showed a normal diurnal rhythm of free corticosterone and a similar response to swim stress.…”

“…First, CRH-R1 antagonists are now extensively discussed as new therapeutical agents in the treatment of depression and anxiety. In various animal models, nonpeptidergic CRH-R1 antagonists, such as CP-154,526, antalarmin, SSR125543A, and NBI 30775, indeed demonstrate antidepressant and anxiolytic properties after acute or chronic administration (Deak et al, 1999;Lundkvist et al, 1996;Schulz et al, 1996;Griebel et al, 1998Griebel et al, , 2002Arborelius et al, 2000;Millan et al, 2001;Heinrichs et al, 2002;Gutman et al, 2003). Importantly, a first study in 20 depressed patients showed the therapeutical potential of the CRH-R1 antagonist NBI 30775 (Zobel et al, 2000;NBI 30775 is referred to as R121919 in this study).…”

Role of corticotropin releasing factor in anxiety disorders: A translational research perspective

“…Various stressors (e.g., 24 h social isolation, repeated tail pinch, bright light, acute and repeated restraint, footshock) increase startle magnitude and/or reduce PPI in rats (Brake et al, 2000;de Jongh et al, 2003;Faraday, 2002;Sipos et al, 2000). CRF receptor activation is necessary for the effects of many of these stressors (e.g., light, shock, restraint) on other behaviors such as locomotion, avoidance and freezing (Bakshi and Kalin, 2000;Bakshi et al, 2002;Gutman et al, 2003;Heinrichs et al, 2002;Ho et al, 2001;Le et al, 2002) and on startle in the case of light stress (de Jongh et al, 2003) and perhaps FPS (de Jongh et al, 2003;Schulz et al, 1996;Swerdlow et al, 1989;Walker and Davis, 2002a;Risbrough and Geyer, 2005). The extended amygdala (specifically the bed nucleus stria terminalis) is required for both CRFand stress-induced increases in startle (de Jongh et al, 2003;Gewirtz et al, 1998;Lee and Davis, 1997;Toufexis et al, this volume).…”