Effects of chronic ethanol intake and its withdrawal on the expression and phosphorylation of the creb gene transcription factor in rat cortex.

This investigation examined the effects of chronic ethanol treatment (15 days) and its withdrawal (24 h) on the expression and phosphorylation of cyclic AMP-response element-binding (CREB) protein in the rat cortex. The effects of chronic ethanol treatment and withdrawal on protein kinase A (PKA) activity and on the expression of the regulatory RII-beta- and the alpha-subtype catalytic subunits of PKA, and on the protein expression of Ca(2+)/calmodulin-dependent protein kinase IV (CaM kinase IV) and calcineurin in the rat cortex were also investigated. It was found that ethanol withdrawal but not ethanol treatment produced a significant decrease in the phosphorylated CREB (p-CREB) and CaM kinase IV protein levels in the frontal, parietal, and piriform cortex. Ethanol treatment and its withdrawal had no effect on the protein levels of total CREB in the frontal, parietal, and piriform cortex. On the other hand, ethanol treatment produced a significant reduction in the protein levels of CREB, p-CREB, and CaM kinase IV in the cingulate gyrus, and these changes reverted to normal levels during ethanol withdrawal. Total CREB protein levels were significantly higher in the cingulate gyrus during ethanol withdrawal. It was also observed that mRNA levels of CREB were significantly higher in the rat cortex during ethanol withdrawal but not during ethanol treatment. The protein levels of RII-beta- and alpha-subtype catalytic subunits of PKA and PKA activity were not modified in the rat cortex by chronic ethanol treatment and its withdrawal. Furthermore, the expression of calcineurin in the rat cortex was not altered during ethanol treatment and withdrawal. Taken together, these results suggest the possibility that decreased CREB-dependent events in the neurocircuitry of the frontal, parietal, and piriform cortex may play an important role in the phenomenon of alcohol dependence and also that decreased CREB-dependent events in the neurocircuitry of the cingulate gyrus may play a role in alcohol tolerance.