Biomol Ther  
Evodiamine Reduces Caffeine-Induced Sleep Disturbances and Excitation in Mice
Yong-Hyun Ko, Kyu-Yeon Shim, Seok-Yong Lee and Choon-Gon Jang*
Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
E-mail: jang@skku.edu
Tel: +82-31-290-7780, Fax: +82-31-292-8800
The first two authors contributed equally to this work.
Received: July 17, 2017; Revised: September 11, 2017; Accepted: September 14, 2017; Published online: January 9, 2018.
© The Korean Society of Applied Pharmacology. All rights reserved.

Abstract
Worldwide, caffeine is among the most commonly used stimulatory substances. Unfortunately, significant caffeine consumption is associated with several adverse effects, ranging from sleep disturbances (including insomnia) to cardiovascular problems. This study investigates whether treatment with the Evodia rutaecarpa aqueous extract (ERAE) from berries and its major molecular component, evodiamine, can reduce the adverse caffeine-induced sleep-related and excitation effects. We combined measurements from the pentobarbital-induced sleep test, the open field test, and the locomotor activity test in mice that had been dosed with caffeine. We found that ERAE and evodiamine administration reduced the degree of caffeine-induced sleep disruption during the sleep test. Additionally, we found that evodiamine significantly inhibits caffeine-induced excitation during the open field test, as well as decreasing hyperlocomotion in the locomotor activity test. Additional in vitro experiments showed that caffeine administration decreased the expression of γ-aminobutyric acid (GABA)A receptor subunits in the mouse hypothalamus. However, evodiamine treatment significantly reversed this expression reduction. Taken together, our results demonstrate that ERAE and its major compound, evodiamine, provide an excellent candidate for the treatment or prevention of caffeine-induced sleep disturbances and excitatory states, and that the mechanism of these beneficial effects acts, at least in part, through the GABAA-ergic system.
Keywords: Evodiamine, Evodia rutaecarpa, Caffeine, γ-aminobutyric acid receptor, Sleep


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