CHOLECYSTOKININ-OCTAPEPTIDE STIMULATES HYPOTHALAMIC-PITUITARY-ADRENALFUNCTION IN RATS - ROLE OF CORTICOTROPIN-RELEASING HORMONE

Peripherally-administered cholecystokinin (CCK) is a profound suppress or of food intake, can promote anxiety, and causes the acute release o f ACTH into plasma. Centrally administered corticotropin-releasing hor mone (CRH), on the other hand, not only represents the principal stimu lus to the pituitary corticotroph cell, but also has been shown to sup press appetite and to be profoundly anxiogenic. Because of the overlap in the effects of peripherally administered CCK and of centrally admi nistered CRH, we report here a study to determine whether sulphated CC K octapeptide (CCK-8) could induce the release of CRH within the centr al nervous system. To accomplish this task, we first assessed the dose -related effects of CCK-8 on ACTH release. Graded doses of CCK-8 (0.1- 10-mu-g/kg BW) given in an iv bolus to freely moving male rats, result ed in a dose-dependent increase of plasma immunoreactive (IR)-ACTH (ED 50: 1-10-mu-g/kg BW). The lowest maximal stimulatory dose of CCK-8 (5- mu-g/kg BW) was used in all subsequent experiments. To evaluate whethe r 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 specif ic, 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 significantly attenuated by L-364,718. A role for the vagal afferents that contain CCK receptors in peripherally administered CCK -mediated hypothalamic-pituitary-adrenal (HPA) axis activation was exa mined in animals that had been pretreated with capsaicin, a potent neu rotoxin that destroys vagal afferents. Plasma IR-ACTH and IR-corticost erone responses in capsaicin-treated animals were significantly lower than those in vehicle treated rats. In subsequent in vivo experiments, pituitary stalk-transected and sham-operated animals were used to eva luate whether CCK-8 stimulates the HPA axis via a centrally mediated m echanism. IR-ACTH and IR-corticosterone responses to iv CCK-8 were sig nificantly reduced in the pituitary stalk-transected compared to sham- operated animals. In further effort to determine whether the central n ervous system was involved in the plasma IR-ACTH response to the perip heral administration of iv CCK-8, we compared the effects of the iv ad ministration of CRH antisera vs. normal rabbit serum on this parameter . IR-ACTH and IR-corticosterone responses to iv CCK-8 were significant ly reduced in the context of pre-treatment 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 t he significant stimulation of IR-ACTH release compared to vehicle, ind icating a direct central effect of CCK. To further examine the locus o f the effects of CCK-8 on HPA axis stimulation, we also investigated t he in vitro response of graded concentrations of CCK-8 on hypothalamic IR-CRH and pituitary IR-ACTH release. Although CCK-8 stimulates hypot halamic CRH secretion in a dose-dependent fashion, it had no effect, r egardless of the dose, on IR-ACTH secretion by dispersed rat anterior pituicytes. We conclude that the HPA axis activation following the per ipheral administration of CCK involves CCK-mediated CRH release occurr ing in part, via activation of CCK receptors on peripherally located v agal afferents. We also conclude that CCK in the central nervous syste m may cause the direct release of CRH from the paraventricular nucleus . These data suggest that CCK effects on pituitary-adrenal function, a nd 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 pathogenesis and symptom compl ex of both eating and anxiety disorders.