Hypothalamic-pituitary adrenal response to cholecystokinin-B receptor agonism is resistant to cortisol feedback inhibition.
Intravenous injection of the cholecystokinin (CCK)-B receptor agonist, pentagastrin, produces robust, dose-dependent release of adrenocorticotropin (ACTH) and cortisol, supporting the hypothesis that CCK-B agonists pharmacologically activate the hypothalamic-pituitary-adrenal (HPA) axis. The mechanism of activation and its physiological relevance remain uncertain. Preliminary data suggest that the ACTH response to pentagastrin may be differentiated from the response to exogenous corticotropin releasing hormone (CRH) by its relative resistance to cortisol feedback inhibition. To more directly test the relationship between cortisol levels and ACTH response to pentagastrin, this study examined responses to pentagastrin (a) during a peak (8 a.m.) and a nadir (4 p.m.) period of endogenous cortisol secretion and (b) when cortisol levels were artificially reduced to low levels by administration of metyrapone. ACTH responses to pentagastrin were identical in the morning and afternoon, despite substantial differences in basal cortisol levels. Suppression of cortisol with metyrapone had little impact on ACTH response to pentagastrin. These data support the hypothesis that CCK-B receptor mediated activation of the HPA axis is relatively resistant to cortisol feedback inhibition. This differentiates it from CRH-mediated activation and raises the possibility that CCK could contribute to acute activation of the HPA axis even in the face of elevated basal cortisol levels, such as those seen in chronic stress or some psychiatric disorders.
Abelson
J L
JL
Department of Psychiatry, Anxiety Disorders Program, Mental Health Research Institute, University of Michigan, Ann Arbor, MI 48109, USA. jabelson@umich.edu
Young
E A
EA
D000311:Adrenal Glands / Q000187:drug effects / Q000502:physiology*; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000328:Adult; D002940:Circadian Rhythm; D004351:Drug Resistance; D025461:Feedback, Physiological; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D008297:Male; D008797:Metyrapone; D010418:Pentagastrin; D010902:Pituitary Gland / Q000187:drug effects / Q000502:physiology*; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000819:agonists* / Q000187:drug effects / Q000502:physiology
D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D000324:Adrenocorticotropic Hormone; D010418:Pentagastrin; D006854:Hydrocortisone; D008797:Metyrapone