Research articleThe non-peptide CRH1-antagonist CP-154,526 elicits a paradoxical route-dependent activation of the HPA axis

•The non-peptide CRH1-antagonist CP-154,526 (CP) was administered to rats intraperitoneally or intraarterially.•Intraarterial administration suppressed levels of ACTH induced by stress, while intraperitoneal administration did not.•Intraperitoneal, but not intraarterial injection of CP dramatically increased ACTH levels in the blood by itself.•Intraperitoneal injection of CP increased blood pressure and expression of c-fos in paraventricular hypothalamic nucleus.

The corticotropin-releasing hormone (CRH) plays an important role in mediating physiological response to stress and is thought to be involved in the development of various psychiatric disorders. In this paper, we compare the differences between the effect of intraperitoneal (i.p.) and intraarterial (i.a.) administration of the non-peptide CRH1 antagonist CP-154,526 (CP) (10 and 20 mg/kg) on plasma adrenocorticotropic hormone levels (ACTH), heart rate, MAP, and c-Fos expression in the paraventricular nucleus of the hypothalamus. Intraperitoneal, but not i.a., injection of CP resulted in an increase in plasma ACTH (from 105 ± 13 to 278 ± 51 pg/ml after 20 mg/kg). This effect was accompanied by a dramatic increase in c-Fos expression in cells immunoreactive for CRH in the paraventricular nucleus of the hypothalamus. When the drug was administered i.p., CP-induced activation of the HPA appears to mask the inhibitory effect of CP on stress-induced ACTH secretion, an effect which was readily apparent when the drug was given i.a. Intraperitoneal administration of CP also increased the baseline MAP which may account for previous reports that treatment with this drug attenuated the increases associated with stress. CP given by either route had no effect on baseline heart rate or stress-induced tachycardia. Thus, in all studies in which CP 154,526 is given, the route of delivery must be given careful consideration.