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 CCK-8 on ACTH release. Graded doses of CCK-8 (0.1-10 micrograms/kg BW) given in an i.v. bolus to freely moving male rats, resulted in a dose-dependent increase of plasma immunoreactive (IR)-ACTH (ED50: 1-10 micrograms/kg BW). The lowest maximal stimulatory dose of CCK-8 (5 micrograms/kg BW) was used in all subsequent experiments. To evaluate whether CCK-induced ACTH secretion was mediated by a peripheral CCK receptor, an i.v. bolus injection of vehicle or L-364,718 (1 mg/kg BW), a specific, highly potent peripheral CCK receptor antagonist, was given before the i.v. 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 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 rats. 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 i.v. CCK-8 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 i.v. CCK-8, we compared the effects of the i.v. administration of CRH antisera vs. normal rabbit serum on this parameter. IR-ACTH and IR-corticosterone responses to i.v. CCK-8 were significantly reduced in the context of pretreatment with CRH antisera compared to the administration of normal rabbit serum.(ABSTRACT TRUNCATED AT 400 WORDS)
Kamilaris
T C
TC
Clinical Neuroendocrinology Branch, National Institute of Mental Health, National Institute of Child Health and Human Development, Bethesda, Maryland 20892.
Johnson
E O
EO
Calogero
A E
AE
Kalogeras
K T
KT
Bernardini
R
R
Chrousos
G P
GP
Gold
P W
PW
D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D008297:Male; D010913:Pituitary-Adrenal System / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D011949:Receptors, Cholecystokinin / Q000502:physiology; D012844:Sincalide / Q000494:pharmacology*
D011949:Receptors, Cholecystokinin; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D012844:Sincalide