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A Retinoic Acid Receptor Antagonist Suppresses Brain Retinoic Acid Receptor Overexpression and Reverses a Working Memory Deficit Induced by Chronic Ethanol Consumption in Mice
Author(s) -
Alfos Serge,
Boucheron Catherine,
Pallet Véronique,
Higueret Denise,
Enderlin Valérie,
Béracochéa Daniel,
Jaffard Robert,
Higueret Paul
Publication year - 2001
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.2001.tb02154.x
Subject(s) - retinoic acid , retinoid , retinoic acid receptor , endocrinology , medicine , antagonist , retinoid x receptor , receptor , receptor antagonist , chemistry , neurochemical , pharmacology , biology , biochemistry , nuclear receptor , transcription factor , gene
Background: Chronic ethanol consumption induces disorders in the biosynthesis of retinoic acid, an active derivative of vitamin A. Recent evidence suggests that an alteration in the retinoic acid signaling pathway leads to impairments in learning and memory in adult mice. We have previously shown that chronic ethanol consumption in mice produces an increased expression of the brain retinoic acid receptor β (RARβ) mRNA. These results prompted us to examine whether suppressing the overexpression of retinoid receptors in alcohol‐treated mice by RAR antagonist administration would reverse their cognitive impairment. Methods: After 10 months of ethanol consumption (12% v/v in drinking water), C57BL/6 mice were submitted to a working memory task in a T‐maze. Then, mice of the control and the ethanol‐treated groups received an RARβ antagonist (CD2665 0.6 mg/kg) for 22 days. The behavioral effect of CD2665 administration was evaluated on a spontaneous alternation task and the neurochemical effect was measured by quantifying the mRNA expression of RARα, RARβ, retinoid X receptor (RXRβ/γ) and tissue transglutaminase (tTG; a retinoic acid‐target gene). Results: Mice submitted to ethanol treatment exhibited a progressive decrease in spontaneous alternation rates over successive trials. Moreover, these mice displayed an increased expression of brain RARβ and RXRβ/γ mRNA, together with an increased level of tTG mRNA and enzymatic activity. The administration of CD2665 to alcohol‐treated mice totally reversed the working memory deficit and suppressed the overexpression of brain RARβ, RXRβ/γ and tTG mRNA, whereas the same treatment in control mice decreased only the RARβ mRNA level without affecting memory performance. Conclusion: These data point to the potential role of the retinoid signaling pathway in memory processes and suggest that the overexpression of brain RARβ and RXRβ/γ could be responsible, at least in part, for some memory impairments observed during chronic ethanol consumption.