A retinoic acid receptor antagonist suppresses brain retinoic acid receptor overexpression and reverses a working memory deficit induced by chronic ethanol consumption in mice

Background: Chronic ethanol consumption induces disorders in the biosynthes is of retinoic acid, an active derivative of vitamin A. Recent evidence sug gests that an alteration in the retinoic acid signaling pathway leads to im pairments in learning and memory in adult mice. We have previously shown th at chronic ethanol consumption in mice produces an increased expression of the brain retinoic acid receptor beta (RAR beta) mRNA. These results prompt ed us to examine whether suppressing the overexpression of retinoid recepto rs in alcohol-treated mice by RAR antagonist administration would reverse t heir 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, m ice of the control and the ethanol-treated groups received an RAR beta anta gonist (CD2665 0.6 mg/kg) for 22 days. The behavioral effect of CD2665 admi nistration was evaluated on a spontaneous alternation task and the neuroche mical effect was measured by quantifying the mRNA expression of RAR alpha, RAR beta, retinoid X receptor (RXR beta/gamma) and tissue transglutaminase (tTG; a retinoic acid-target gene). Results: Mice submitted to ethanol treatment exhibited a progressive decrea se in spontaneous alternation rates over successive trials. Moreover, these mice displayed an increased expression of brain RAR beta and RXR beta/gamm a 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 RAR beta , RXR beta/gamma and tTG mRNA, whereas the same treatment in control mice d ecreased only the RAR beta mRNA level without affecting memory performance. Conclusion: These data point to the potential role of the retinoid signalin g pathway in memory processes and suggest that the overexpression of brain RAR beta and RXR beta/gamma could be responsible, at least in part, for som e memory impairments observed during chronic ethanol consumption.