Cholecystokinin-octapeptide stimulates hypothalamic- pituitary-adrenal function in rats: Role of corticotropin-releasing hormone

Peripherally-administered cholecystokinin (CCK) is a profound suppressor of food intake, can promote anxiety, and causes the acute release of ACTH into plasma. Centrally administered corticotropin-releasing hormone (CRH), on the other hand, not only represents the principal stimulus to the pituitary corticotroph cell, but also has been shown to suppress appetite and to be profoundly anxiogenic. Because of the overlap in the effects of peripherally administered CCK and of centrally administered CRH, we report here a study to determine whether sulphated CCK octapeptide (CCK-8) could induce the release of CRH within the central nervous system. To accomplish this task, we first assessed the dose-related effects of CCK8 on ACTH release. Graded doses of CCK8 (0.1-10 µg/kg BW) given in an iv bolus to freely moving male rats, resulted in a dose-dependent increase of plasma immunoreactive (IR)- ACTH (ED50: 1-10 µg/kg BW). The lowest maximal stimulatory dose of CCK-8 (5 µg/kg BW) was used in all subsequent experiments. To evaluate whether CCK-induced ACTH secretion was mediated by a peripheral CCK receptor, an iv bolus injection of vehicle or L-364, 718 (1 mg/kg BW), a specific, highly potent peripheral CCK receptor antagonist, was given before the iv administration of CCK-8 or vehicle. Plasma IR-ACTH response to CCK-8 was sianificantly attenuated bv L-364.718. A role for the vagal afferer & that contain CCK receptors in peripherally administered CCK-mediated hypothalamic-pituitary-adrenal (HPA) axis activation was examined in animals that had been pretreated with capsaicin, a potent neurotoxin that destroys vagal afferents. Plasma IR-ACTH and IR-corticosterone responses in capsaicin-treated animals were significantly lower than those in vehicle treated rate. In subsequent in vivo experiments, pituitary stalk-transected and sham-operated animals were used to evaluate whether CCK-8 stimulates the HPA axis via a centrally mediated mechanism. IR-ACTH and IR-corticosterone responses to iv CCKS were significantly reduced in the pituitary stalk-transected compared to sham-operated animals. In further effort to determine whether the central nervous system was involved in the plasma IR-ACTH response to the peripheral administration of iv CCK-8, we compared the effects of the iv administration of CRH antisera vs. normal rabbit serum on this parameter. IR-ACTH and IR-corticosterone responses to iv CCK-8 were significantly reduced in the context of pretreatment with CRH antisera compared to the administration of normal rabbit serum. We also showed that the intracerebroventricular administration of CCK-8 (250 ng) resulted in the significant stimulation of IR-ACTH release compared to vehicle, indicating a direct central effect of CCK. To further examine the locus-of the effects of CCK-8 on HPA axis stimulation, we also investigated the in vitro response of graded concentrations of CCK-8 on hypothalamic IR-CRH and pituitary IR-ACTH release. Although CCK-8 stimulates hypothalamic CRH secretion in a dose-dependent fashion, it had no effect, regardless of the dose, on IR-ACTH secretion by dispersed rat anterior pituicytes. We conclude that the HPA axis activation following the peripheral administration of CCK involves CCK-mediated CRH release occurring in part, via activation of CCK receptors on peripherally located vagal afferents. We also conclude that CCK in the central nervous system may cause the direct release of CRH from the paraventricular nucleus. These data suggest that CCK effects on pituitary-adrenal function, and perhaps food intake and anxiety, may be mediated, at least in part, via CRH. These data are of potential clinical relevance in the light of data linking both CCK and CRH to the pathogenesia and symptom complex of both eating and anxiety disorders.