Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA, USA.
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.
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.
中枢神经系统 (CNS) 的化学保护依赖于血脑屏障 (BBB) 对小分子物质进入的离散控制。奇怪的是，尽管有些药物几乎没有通过 BBB，但仍会引起 CNS 副作用。为了研究这一现象，我们想知道高度富含 BBB 的药物外排转运蛋白 MDR1 是否在控制药物和内源性分子的中枢神经系统内稳态方面具有双重功能。如果这是真的，那么不透血脑屏障的药物可能会通过影响大脑内源性分子的水平来引起行为改变。我们使用计算、遗传和药理学方法在多种生物中进行研究，证明了 BBB 定位的外排转运蛋白对于调节大脑内源性类固醇和类固醇调节行为（果蝇中的睡眠和小鼠中的焦虑）的水平至关重要。此外，我们还表明，与 MDR1 相互作用的药物与人类的焦虑相关行为有关。我们提出了一种常见处方药产生常见行为副作用的一般机制：药物挑战 BBB 外排转运蛋白会破坏大脑内源性底物的水平，并表明 BBB 参与了行为调节。
