title: The Differential Binding of Antipsychotic Drugs to the ABC Transporter P-Glycoprotein Predicts Cannabinoid-Antipsychotic Drug Interactions.
abstract: Cannabis use increases rates of psychotic relapse and treatment failure in schizophrenia patients. Clinical studies suggest that cannabis use reduces the efficacy of antipsychotic drugs, but there has been no direct demonstration of this in a controlled study. The present study demonstrates that exposure to the principal phytocannabinoid, Δ9-tetrahydrocannabinol (THC), reverses the neurobehavioral effects of the antipsychotic drug risperidone in mice. THC exposure did not influence D2and 5-HT2Areceptor binding, the major targets of antipsychotic action, but it lowered the brain concentrations of risperidone and its active metabolite, 9-hydroxy risperidone. As risperidone and its active metabolite are excellent substrates of the ABC transporter P-glycoprotein (P-gp), we hypothesized that THC might increase P-gp expression at the blood-brain barrier (BBB) and thus enhance efflux of risperidone and its metabolite from brain tissue. We confirmed that the brain disposition of risperidone and 9-hydroxy risperidone is strongly influenced by P-gp, as P-gp knockout mice displayed greater brain concentrations of these drugs than wild-type mice. Furthermore, we demonstrated that THC exposure increased P-gp expression in various brain regions important to risperidone's antipsychotic action. We then showed that THC exposure did not influence the neurobehavioral effects of clozapine. Clozapine shares a very similar antipsychotic mode of action to risperidone, but unlike risperidone is not a P-gp substrate. Our results imply that clozapine or non-P-gp substrate antipsychotic drugs may be better first-line treatments for schizophrenia patients with a history of cannabis use.
authors.affiliation: The Brain and Mind Centre, University of Sydney, Camperdown, NSW, Australia.|Discipline of Pharmacology, School of Medical Science, University of Sydney, Camperdown, NSW, Australia.
authors.forename: Natalia I
authors.initials: NI
authors.lastname: Brzozowska
authors.affiliation: Discipline of Pharmacology, School of Medical Science, University of Sydney, Camperdown, NSW, Australia.
authors.forename: Erik J
authors.initials: EJ
authors.lastname: de Tonnerre
authors.affiliation: Discipline of Pharmacology, School of Medical Science, University of Sydney, Camperdown, NSW, Australia.
authors.forename: Kong M
authors.initials: KM
authors.lastname: Li
authors.affiliation: Bosch Mass Spectrometry Facility, Bosch Institute, Sydney Medical School, University of Sydney, Camperdown, NSW, Australia.
authors.forename: Xiao Suo
authors.initials: XS
authors.lastname: Wang
authors.affiliation: The Brain and Mind Centre, University of Sydney, Camperdown, NSW, Australia.|Discipline of Pharmacology, School of Medical Science, University of Sydney, Camperdown, NSW, Australia.
authors.forename: Aurelie A
authors.initials: AA
authors.lastname: Boucher
authors.affiliation: The Brain and Mind Centre, University of Sydney, Camperdown, NSW, Australia.|ANSTO Life Sciences, Australian Nuclear Science and Technology Organisation, Kirrawee, NSW, Australia.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Callaghan
authors.affiliation: Australian Microscopy and Microanalysis Research Facility, The Brain and Mind Centre, University of Sydney, Camperdown, NSW, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Kuligowski
authors.affiliation: Discipline of Pharmacology, School of Medical Science, University of Sydney, Camperdown, NSW, Australia.
authors.forename: Alex
authors.initials: A
authors.lastname: Wong
authors.affiliation: The Brain and Mind Centre, University of Sydney, Camperdown, NSW, Australia.|Discipline of Pharmacology, School of Medical Science, University of Sydney, Camperdown, NSW, Australia.
authors.forename: Jonathon C
authors.initials: JC
authors.lastname: Arnold
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003024:Clozapine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D020891:Raclopride / Q000493:pharmacokinetics; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects; D018967:Risperidone / Q000494:pharmacology; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014150:Antipsychotic Agents; D016760:Proto-Oncogene Proteins c-fos; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D014316:Tritium; D020891:Raclopride; D013759:Dronabinol; D003024:Clozapine; D018967:Risperidone