The central nervous system is particularly susceptible to alcohol effects and toxicity. Glial cells constitute the most common cell type in the brain and play critical roles in normal brain function and during infection and injury. Astrocytes in particular seem to be important targets for alcohol neurotoxicity during both development and in adulthood. To gain more insight into alcohol-mediated effects on astrocytes at the molecular level, gene expression in rat C6 glial cells was studied in the presence or absence of ethanol. The differential display of mRNA technique was used to screen the expressed genes in ethanol-treated rat C6 cells before and after treatment with lipopolysaccharide (LPS) combined with phorbol-12-myristate-13-acetate (PMA), conditions that mimic an infectious inflammatory state and cause immunologic activation. The present data show that fibronectin appeared as a major gene whose expression is increased in C6 cells by LPS plus PMA stimulation and decreased by chronic ethanol exposure, both in mRNA and protein levels. Fibronectin is a dimeric glycoprotein found in the extracellular matrix of most tissues, in the blood, and on cell surfaces and is involved in many cellular processes. These results show that chronic exposure to ethanol is associated with changes in astrocyte properties during immunologic activation that reduce fibronectin expression. The discovery of astrocyte fibronectin expression as a potential regulated target for chronic alcohol abuse may be useful in understanding, preventing, and treating some brain disorders associated with alcohol abuse and alcoholism.