Evolutionarily Conserved Roles for Blood-Brain Barrier Xenobiotic Transporters in Endogenous Steroid Partitioning and Behavior

Cell Rep. 2017 Oct 31;21(5):1304-1316. doi: 10.1016/j.celrep.2017.10.026.


Central nervous system (CNS) chemical protection depends upon discrete control of small-molecule access by the blood-brain barrier (BBB). Curiously, some drugs cause CNS side-effects despite negligible transit past the BBB. To investigate this phenomenon, we asked whether the highly BBB-enriched drug efflux transporter MDR1 has dual functions in controlling drug and endogenous molecule CNS homeostasis. If this is true, then brain-impermeable drugs could induce behavioral changes 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.

Keywords: behavior; blood brain barrier; central nervous system; drug side effect mechanisms; drug transporters; endobiotics; steroid hormones; toxicology.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / chemistry
  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / chemistry
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Aldosterone / chemistry
  • Aldosterone / metabolism
  • Animals
  • Behavior, Animal / drug effects
  • Binding Sites
  • Biological Evolution
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / metabolism*
  • Brain / drug effects
  • Brain / metabolism
  • Central Nervous System / metabolism*
  • Cyclosporine / pharmacology
  • Databases, Chemical
  • Drosophila
  • Drosophila Proteins / chemistry
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Ecdysterone / chemistry
  • Ecdysterone / metabolism
  • Gonadal Steroid Hormones / analysis
  • Gonadal Steroid Hormones / metabolism*
  • Male
  • Molecular Docking Simulation
  • Rats
  • Substrate Specificity
  • Xenobiotics / chemistry
  • Xenobiotics / metabolism*


  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Drosophila Proteins
  • Gonadal Steroid Hormones
  • Xenobiotics
  • mdr65 protein, Drosophila
  • Aldosterone
  • Ecdysterone
  • Cyclosporine