A retinoic acid receptor antagonist suppresses brain retinoic acid receptor overexpression and reverses a working memory deficit induced by chronic ethanol consumption in mice.
Alfos S(1), Boucheron C, Pallet V, Higueret D, Enderlin V, Béracochéa D, Jaffard R, Higueret P.
Author information:
(1)Unité de Nutrition et Signalisation Cellulaire, Institut des Sciences et
Techniques des Aliments de Bordeausc, Université Bordeaux I, Talence, France.
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 beta (RARbeta) 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 RARbeta 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 RARalpha, RARbeta, retinoid X
receptor (RXRbeta/gamma) 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 RARbeta and RXRbeta/gamma 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 RARbeta, RXRbeta/gamma
and tTG mRNA, whereas the same treatment in control mice decreased only the
RARbeta 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 RARbeta
and RXRbeta/gamma could be responsible, at least in part, for some memory
impairments observed during chronic ethanol consumption.