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Chronic stress and antidepressant treatment have opposite effects on P-glycoprotein at the blood–brain barrier: an experimental PET study in rats

By Johan A. den Boer, Girstaute Dagyte, Tim de Jager, Anniek K.D. Visser, Aren van Waarde, Antoon T.M. Willemsen, Fokko J. Bosker, Onno L. de Klerk, Rudi A. Dierckx and Peter Meerlo

Abstract

The multi-drug efflux transporter P-glycoprotein is expressed in high concentrations at the blood–brain barrier and has a major function in the transport of drugs. In a recent PET-study evidence was found for an increased function of P-glycoprotein at the blood–brain barrier in medicated patients suffering from major depressive disorder. We used small-animal PET and [11C]-verapamil to study P-glycoprotein function at the blood–brain barrier of rats, either being administered as venlafaxine, an antidepressant, or subjected to chronic stress, a factor contributing to the development of depression. In a first experiment, male Wistar rats underwent a three-week foot shock procedure as a model of human depression. In a second experiment, rats were chronically treated with the antidepressant venlafaxine (25 mg/kg/d via an implanted osmotic minipump). In both experiments, a [11C]-verapamil PET scan was performed. In the chronically stressed rats, the distribution volume (VT) of [11C]-verapamil was significantly increased, whereas treatment with venlafaxine had the opposite effect and caused a significant reduction in VT. The changes in VT could not be attributed to the influx rate constant (K1). Our data suggest that P-glycoprotein function at the blood–brain barrier is inhibited by chronic stress and increased by chronic administration of venlafaxine.

Year: 2010
OAI identifier: oai:ub.rug.nl:dbi/4c750e03b9e75
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