Retinoic acid receptor antagonist LE540 attenuates wakefulness via the dopamine D1 receptor in mice

• Published in: Brain research 2011-11, Vol.1423, p.10-16
• Main Authors: Kitaoka, Kazuyoshi, Shimizu, Mika, Shimizu, Noriyuki, Chikahisa, Sachiko, Nakagomi, Madoka, Shudo, Koichi, Yoshizaki, Kazuo, Séi, Hiroyoshi
• Format: Article
• Language: English
• Subjects: 3,4-Dihydroxyphenylacetic Acid - metabolism; Animals; antagonists; Biological and medical sciences; brain; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Delta Rhythm - drug effects; Dibenzazepines - pharmacology; Dopamine; Dopamine - metabolism; dopamine receptors; Electroencephalography; eyes; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; genes; high performance liquid chromatography; homovanillic acid; Homovanillic Acid - metabolism; Male; metabolites; Mice; Mice, Inbred C57BL; Neurology; Receptors, Dopamine D1 - metabolism; Receptors, Retinoic Acid - antagonists & inhibitors; Retinoic acid; Sleep; Sleep Stages - drug effects; Sleep. Vigilance; Time Factors; tyrosine; Vertebrates: nervous system and sense organs; vitamin A; vitamin deficiencies; Wakefulness; Wakefulness - drug effects; Western blotting
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2011.09.023

Abstract Vitamin A is a common lipophilic vitamin, and its function is mainly mediated by the binding of its metabolite retinoic acid to retinoic acid receptors (RARs) and retinoid X receptors. Recently, it was reported that the expression of the RARb (an RAR subtype) gene determines the contribution of the delta oscillation in the sleep electroencephalogram (EEG) patterns in mice. We also reported that 4-week dietary deficiency of vitamin A (VAD) causes the attenuation of delta power in sleep and spontaneous activity in mice. However, our previous study could not clarify whether the attenuation of delta power by VAD is attributed to the suppression of RARs. To address this problem, we investigated whether the chronic administration of LE540 (30 mg/kg/day), an antagonist of RARs, for 1 or 4 weeks attenuated EEG delta power during sleep in mice. Consequently, 4-week LE540 administration induced a significant attenuation of wakefulness and delta power in non-rapid eye movement sleep. Western blot analysis revealed a significant decrease in the expression of dopamine D1 receptor (D1DR) in the striatum and tyrosine hydroxylase in the midbrain of mice that were administered LE540 for 4 weeks. High-performance liquid chromatography analysis of striatal tissue revealed a significant decrease in the homovanillic acid/dopamine ratio. Meanwhile, dopamine levels did not change in these mice. Our results suggest that the 4-week antagonism of RARs induces the attenuation of delta power. However, the attenuation of delta power may be elicited indirectly by the decrease of wakefulness followed by the hypo-expression of dopamine receptors especially D1DR.