title: Regional increase in P-glycoprotein function in the blood-brain barrier of patients with chronic schizophrenia: a PET study with [(11)C]verapamil as a probe for P-glycoprotein function.
abstract: P-glycoprotein (P-gp), a major efflux pump in the blood-brain barrier (BBB) has a profound effect on entry of drugs, peptides and other substances into the central nervous system (CNS). The brain's permeability can be negatively influenced by modulation of the transport function of P-gp. Inflammatory mediators play a role in schizophrenia, and may be able to influence the integrity of the BBB, via P-gp modulation. We hypothesized that P-gp function in the BBB is changed in patients with schizophrenia. Positron-emission tomography was used to measure brain uptake of [(11)C]verapamil, which is normally extruded from the brain by P-gp. We found that patients with chronic schizophrenia under treatment with antipsychotic drugs compared with healthy controls showed a significant decrease in [(11)C]verapamil uptake in the temporal cortex, the basal ganglia, and the amygdala, and amygdalae, and a trend towards a significant decrease was seen throughout the brain. The decrease of [(11)C]verapamil uptake correlates with an increased activity of the P-gp pump. Increased P-gp activity may be a factor in drug resistance in schizophrenia, induced by the use of antipsychotic agents.
authors.affiliation: Department of Psychiatry, University Medical Center Groningen (UMCG), P.O. Box 30.001, 9700 RB Groningen, The Netherlands. o.l.klerk@ngmb.umcg.nl
authors.forename: Onno L
authors.initials: OL
authors.lastname: de Klerk
authors.forename: Antoon T M
authors.initials: AT
authors.lastname: Willemsen
authors.forename: Fokko J
authors.initials: FJ
authors.lastname: Bosker
authors.forename: Anna L
authors.initials: AL
authors.lastname: Bartels
authors.forename: N Harry
authors.initials: NH
authors.lastname: Hendrikse
authors.forename: Johan A
authors.initials: JA
authors.lastname: den Boer
authors.forename: Rudy A
authors.initials: RA
authors.lastname: Dierckx
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000704:Analysis of Variance; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging* / Q000378:metabolism*; D001931:Brain Mapping; D002250:Carbon Radioisotopes; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D049268:Positron-Emission Tomography / Q000379:methods; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology*; D014700:Verapamil; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002250:Carbon Radioisotopes; D014700:Verapamil