Previous studies from our laboratory revealed that acute ethanol exposure inhibits phosphorylation of mitogen-activated protein (MAP) kinase and extracellular signal-regulated kinases (ERK) in mice. In the present study, we have further investigated effect of chronic administration of ethanol on tyrosine kinase phosphorylation of GABA(A) receptor subunits in the mouse cultured cortical neurons. We observed that there was an up-regulation in tyrosine kinase phosphorylation of the GABA(A) receptor beta(2) and gamma(2) subunits following chronic ethanol exposure, whereas there was no effect on alpha(1) subunit of the GABA(A) receptor in the cultured cortical neurons of mice as determined by Western blotting. These results suggest a potential role for tyrosine kinase phosphorylation of some of the GABA(A) receptor subunits in chronic ethanol-induced tolerance and dependence.