Chronic stress and antidepressant treatment have opposite effects on P-glycoprotein at the blood-brain barrier: an experimental PET study in rats.
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 [(11)C]-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 [(11)C]-verapamil PET scan was performed. In the chronically stressed rats, the distribution volume (V(T)) of [(11)C]-verapamil was significantly increased, whereas treatment with venlafaxine had the opposite effect and caused a significant reduction in V(T). The changes in V(T) could not be attributed to the influx rate constant (K(1)). Our data suggest that P-glycoprotein function at the blood-brain barrier is inhibited by chronic stress and increased by chronic administration of venlafaxine.
de Klerk
Onno L
OL
Department of Psychiatry, University Medical Center Groningen (UMCG), Groningen, The Netherlands. o.l.klerk@ngmb.umcg.nl
Bosker
Fokko J
FJ
Willemsen
Antoon T M
AT
Van Waarde
Aren
A
Visser
Anniek K D
AK
de Jager
Tim
T
Dagyte
Girstaute
G
den Boer
Johan A
JA
Dierckx
Rudi A
RA
Meerlo
Peter
P
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage* / Q000097:blood; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D003511:Cyclohexanols / Q000008:administration & dosage* / Q000097:blood; D008297:Male; D023421:Models, Animal; D049268:Positron-Emission Tomography; D051381:Rats; D017208:Rats, Wistar; D013315:Stress, Psychological / Q000378:metabolism*; D013997:Time Factors; D000069470:Venlafaxine Hydrochloride; D014700:Verapamil / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000928:Antidepressive Agents; D003511:Cyclohexanols; D000069470:Venlafaxine Hydrochloride; D014700:Verapamil