title: Retinoic acid receptor antagonist LE540 attenuates wakefulness via the dopamine D1 receptor in mice.
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 (30mg/kg/day), an antagonist of RARs, for 1 or 4weeks 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 4weeks. 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.
authors: Department of Physiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan. kitaoka@basic.med.tokushima-u.ac.jp
authors: Kazuyoshi
authors: K
authors: Kitaoka
authors: Mika
authors: M
authors: Shimizu
authors: Noriyuki
authors: N
authors: Shimizu
authors: Sachiko
authors: S
authors: Chikahisa
authors: Madoka
authors: M
authors: Nakagomi
authors: Koichi
authors: K
authors: Shudo
authors: Kazuo
authors: K
authors: Yoshizaki
authors: Hiroyoshi
authors: H
authors: Séi
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003700:Delta Rhythm / Q000187:drug effects; D003984:Dibenzazepines / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D004569:Electroencephalography; D005786:Gene Expression Regulation / Q000187:drug effects; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors*; D012894:Sleep Stages / Q000187:drug effects; D013997:Time Factors; D014851:Wakefulness / Q000187:drug effects*
chemical_list: D003984:Dibenzazepines; C104183:LE 540; D017447:Receptors, Dopamine D1; D018168:Receptors, Retinoic Acid; D015102:3,4-Dihydroxyphenylacetic Acid; D004298:Dopamine; D006719:Homovanillic Acid