Metoclopramide as pharmacological tool to assess vasopressinergic co-activation of the hypothalamus–pituitary–adrenal (HPA) axis: A study in healthy volunteers

• Published in: European neuropsychopharmacology Vol. 20; no. 12; pp. 866 - 874
• Main Authors: Jacobs, G.E, Hulskotte, E.G.J, de Kam, M.L, Zha, G, Jiang, J, Hu, P, Zhao, Q, van Pelt, J, Goekoop, J.G, Zitman, F.G, van Gerven, J.M.A
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-12-2010
• Subjects: Adult; Corticotropin-releasing hormone; Cross-Over Studies; Double-Blind Method; HPA axis; Humans; Hydrocortisone - blood; Hypothalamo-Hypophyseal System - drug effects; Hypothalamo-Hypophyseal System - metabolism; Internal Medicine; Male; Metoclopramide; Metoclopramide - pharmacology; Pharmacodynamics; Pharmacokinetics; Pharmacological function test; Pituitary-Adrenal System - drug effects; Pituitary-Adrenal System - metabolism; Psychiatry; Vasopressin; Vasopressins - blood; Young Adult; Pharmacodynamics; HPA axis; Pharmacological function test; Pharmacokinetics; Metoclopramide; Vasopressin
• ISSN: 0924-977X; 1873-7862
• DOI: 10.1016/j.euroneuro.2010.06.009

Abstract The synthetic vasopressin (AVP) analogue desmopressin (dDAVP) has been used as pharmacological function test to quantify vasopressinergic co-activation of the hypothalamus – pituitary – adrenal (HPA) axis in the past. Such exogenous vasopressinergic stimulation may induce confounding cardiovascular, pro-coagulatory and anti-diuretic effects and low endogenous corticotrophin-releasing-hormone (CRH) levels may limit its potential to reliably assess co-activation. Alternatively, the dopamine-2-(D2)-antagonist metoclopramide is believed to induce co-activation indirectly by releasing endogenous AVP. We investigated this indirect co-activation with metoclopramide under conditions of low and enhanced endogenous CRH release in healthy volunteers. A randomized, double-blind, placebo-controlled, four-way crossover study was performed in 12 healthy males. CRH release was induced by administering an oral 5-hydroxytryptophan (5-HTP) 200 mg function test. Co-activation was investigated by administering metoclopramide 10 mg intravenously around the expected maximal effect of 5-HTP. The neuroendocrine effects were compared to those of metoclopramide alone, the 5-HTP test alone and matching placebo. Metoclopramide safely induced HPA-axis activation by itself, and potently synergized 5-HTP-induced corticotrophinergic activation of the HPA axis. These findings are indicative of vasopressinergic co-activation and suggest a role for metoclopramide as a practical function test for co-activation of the HPA axis. However, its application will be hampered pending clarification of the exact pharmacological mechanism by which metoclopramide induces co-activation of the HPA axis.