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

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.

doi:10.1016/j.euroneuro.2010.06.009

« Previous Next »European Neuropsychopharmacology
Volume 20, Issue 12 , Pages 866-874, December 2010

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

G.E. Jacobs
- Centre for Human Drug Research, Leiden, The Netherlands
- Department of Psychiatry, Leiden University Medical Centre, Leiden, The Netherlands
- Corresponding author. Centre for Human Drug Research, Zernikedreef 10, 2333 CL Leiden, The Netherlands. Tel.: +31 71 524 6497; fax: +31 71 524 6499.
E.G.J. Hulskotte
- NV Organon, Part of Schering-Plough Corporation, Department of Clinical Pharmacology and Kinetics, Oss, The Netherlands
M.L. de Kam
- Centre for Human Drug Research, Leiden, The Netherlands
G. Zha
- Clinical Research Center Laboratory, Peking Union Medical College Hospital, Beijing, China
J. Jiang
- Clinical Research Center Laboratory, Peking Union Medical College Hospital, Beijing, China
P. Hu
- Clinical Research Center Laboratory, Peking Union Medical College Hospital, Beijing, China
Q. Zhao
- Clinical Research Center Laboratory, Peking Union Medical College Hospital, Beijing, China
J. van Pelt
- Department of Clinical Chemistry, Leiden University Medical Centre, Leiden, The Netherlands
J.G. Goekoop
- Department of Psychiatry, Leiden University Medical Centre, Leiden, The Netherlands
- Rivierduinen Mental Health Care Organisation, Oegstgeest, The Netherlands
F.G. Zitman
- Department of Psychiatry, Leiden University Medical Centre, Leiden, The Netherlands
J.M.A. van Gerven
- Centre for Human Drug Research, Leiden, The Netherlands

Received 6 January 2010; received in revised form 2 June 2010; accepted 17 June 2010. published online 26 July 2010.

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) 200mg function test. Co-activation was investigated by administering metoclopramide 10mg 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.

Keywords: Metoclopramide, Pharmacological function test, Vasopressin, Pharmacokinetics, Pharmacodynamics, HPA axis