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

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

Author information

1
Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA, USA.
2
Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA, USA; Division of Clinical Pharmacology and Experimental Therapeutics, University of California San Francisco, San Francisco, CA, USA; Department of Anatomy, University of California San Francisco, San Francisco, CA, USA; Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.
3
Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
4
Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA; Institute for Neurodegenerative Disease, University of California San Francisco, San Francisco, CA, USA; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
5
Division of Biological Science, Graduate School of Science, Nagoya University, Japan.
6
Department of Anatomy, University of California San Francisco, San Francisco, CA, USA; Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.
7
Department of Anesthesia, University of Iowa, Iowa City, Iowa, USA.
8
Department of Anatomy, University of California San Francisco, San Francisco, CA, USA; Department of Pharmacology, University of California San Diego, La Jolla, CA, USA. Electronic address: rdaneman@ucsd.edu.
9
Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA, USA. Electronic address: roland.bainton@ucsf.edu.

Abstract

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

PMID:
29091768
PMCID:
PMC5774027
DOI:
10.1016/j.celrep.2017.10.026
[Indexed for MEDLINE]
Free PMC Article

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