TY - JOUR T1 - Evolutionarily conserved roles for blood-brain barrier xenobiotic transporters in endogenous steroid partitioning and behavior JF - bioRxiv DO - 10.1101/131698 SP - 131698 AU - Samantha J. Hindle AU - Roeben N. Munji AU - Elena Dolghih AU - Garrett Gaskins AU - Souvinh Orng AU - Hiroshi Ishimoto AU - Allison Soung AU - Michael DeSalvo AU - Toshihiro Kitamoto AU - Michael J. Keiser AU - Matthew P. Jacobson AU - Richard Daneman AU - Roland J. Bainton Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/04/29/131698.abstract N2 - Optimal brain function depends upon efficient control over the brain entry of blood components; this is provided by the blood-brain barrier (BBB). Curiously, some brain-impermeable drugs can still cause behavioral side effects.To investigate this phenomenon, we asked whether the promiscuous drug efflux transporter Mdr1 has dual functions in transporting drugs and endogenous molecules. If this is true, brain-impermeable drugs may cause behavioral side effects by affecting brain levels of endogenous molecules.Using computational, genetic and pharmacologic approaches across diverse organisms we demonstrate that BBB-localized efflux transporters are critical for regulating brain levels of endogenous steroids, and steroid-regulated behaviors (sleep in Drosophila and anxiety in mice). Furthermore, we show that Mdr1-interacting drugs are associated with anxiety-related behaviors in humans.We propose a general mechanism for common behavioral side effects of prescription drugs: pharmacologically challenging BBB efflux transporters disrupts brain levels of endogenous substrates, and implicates the BBB in behavioral regulation.Abbreviations20-E20-hydroxyecdysoneABCATP-binding CassetteADRsAdverse Drug ReactionsBBBBlood-Brain BarrierBVECbrain vascular endothelial cellsCNScentral nervous systemEcRLBDecdysone receptor ligand binding domainEFenrichment factorMDRmultidrug resistantRhoBRhodamine BSPGSubperineurial gliaAbbreviations20-E20-hydroxyecdysoneABCATP-binding CassetteADRsAdverse Drug ReactionsBBBBlood-Brain BarrierBVECbrain vascular endothelial cellsCNScentral nervous systemEcRLBDecdysone receptor ligand binding domainEFenrichment factorMDRmultidrug resistantRhoBRhodamine BSPGSubperineurial glia ER -