Journal
CELL REPORTS
Volume 21, Issue 5, Pages 1304-1316Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.10.026
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Funding
- UCSF Department of Clinical Pharmacology and Therapeutics [GM007546]
- Department of Anesthesia and Perioperative Care NIH [GM008440]
- NIH [R01GM081863, R21NS082856, GM111126]
- NIEHS [R21 ES021412]
- UCSF Department of Anesthesia and Perioperative Care
- UCSF
- NIH SBIR [GM093456]
- Glenn Foundation
- iPQB
- NSF [IOS1352882]
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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 inmice). 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.
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