The differential binding of antipsychotic drugs to the ABC transporter P-glycoprotein predicts cannabinoid–antipsychotic drug interactions

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dc.contributor.authorBrzozowska, NIen_AU
dc.contributor.authorde Tonnerre, EJen_AU
dc.contributor.authorLi, KMen_AU
dc.contributor.authorWang, XSen_AU
dc.contributor.authorBoucher, AAen_AU
dc.contributor.authorCallaghan, PDen_AU
dc.contributor.authorKuligowski, Men_AU
dc.contributor.authorWong, Aen_AU
dc.contributor.authorArnold, JCen_AU
dc.date.accessioned2024-01-19T05:12:00Zen_AU
dc.date.available2024-01-19T05:12:00Zen_AU
dc.date.issued2017-03-08en_AU
dc.date.statistics2022-08-27en_AU
dc.description.abstractCannabis 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 D2 and 5-HT2A receptor 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. © 2017 American College of Neuropsychopharmacology, published by Springer Nature Limited.en_AU
dc.identifier.citationBrzozowska, N. I., de Tonnerre, E. J., Li, K. M., Wang, X. S., Boucher, A. A., Callaghan, P. D., Kuligowski, M., Wong, A., & Arnold, J. C. (2017). The differential binding of antipsychotic drugs to the ABC transporter P-glycoprotein predicts cannabinoid–antipsychotic drug interactions. Neuropsychopharmacology, 42(11), 2222-2231. doi:10.1038/npp.2017.50en_AU
dc.identifier.issn1740-634Xen_AU
dc.identifier.issue11en_AU
dc.identifier.journaltitleNeuropsychopharmacologyen_AU
dc.identifier.pagination2222-2231en_AU
dc.identifier.urihttps://doi.org/10.1038/npp.2017.50en_AU
dc.identifier.urihttps://apo.ansto.gov.au/handle/10238/15363en_AU
dc.identifier.volume42en_AU
dc.language.isoenen_AU
dc.publisherSpringeren_AU
dc.relation.urihttps://doi.org/10.1038/npp.2017.50en_AU
dc.subjectDrugsen_AU
dc.subjectGlycoproteinsen_AU
dc.subjectTherapyen_AU
dc.subjectPatientsen_AU
dc.subjectSide effectsen_AU
dc.subjectMiceen_AU
dc.subjectBrainen_AU
dc.subjectHazardsen_AU
dc.subjectBlood-brain barrieren_AU
dc.subjectMental disordersen_AU
dc.titleThe differential binding of antipsychotic drugs to the ABC transporter P-glycoprotein predicts cannabinoid–antipsychotic drug interactionsen_AU
dc.typeJournal Articleen_AU
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