Excessive alcohol consumption alters neuronal growth and causes striking elongation of axons and dendrites in several brain regions. This could result from increased sensitivity to neurotrophic factors, since ethanol markedly enhances nerve growth factor (NGF)-and basic fibroblast growth factor (bFGF)-stimulated neurite outgrowth in the neural cell line PC12. The mechanism by which ethanol enhances growth factor responses was investigated by examining activation of mitogen-activated protein kinases (MAP kinases), a key event in growth factor signaling. Ethanol (100 mM) increased NGF-and bFGF-induced activation of MAP kinases. This increase, like ethanol-induced increases in neurite outgrowth, was prevented by down regulation of .3, 6, and E protein kinase C (PKC) isozymes. Since chronic ethanol exposure specifically upregulates 6 and E PKC, these findings suggest that ethanol promotes neurite growth by enhancing growth factor signal transduction through a a or E PKC-regulated pathway.Medical complications of alcohol abuse contribute to more than 20% of hospital admissions in the United States (1). Several neurological disorders are associated with alcoholism and many appear to result from a direct neurotoxic effect of alcohol (2). One mechanism by which alcohol injures the nervous system is by altering the growth of axons and dendrites (neurites). Although early studies showed that ethanol inhibited neurite growth in some neurons (3, 4), several reports (5-10) indicate that ethanol markedly enhances neurite growth in several brain regions. For example, in adult rats, chronic ethanol exposure increases the length of dendrites in cerebellar Purkinje cells and hippocampal dentate granule cells and the number of dendritic spines on dentate granule cells and somatosensory cortical neurons (5-8). Prenatal ethanol exposure increases dendritic arborization in layer Vb somatosensory corticospinal neurons and causes hyperdevelopment of hippocampal dentate granule cell axons (9, 10). Ethanol also enhances neurite outgrowth in cultured cerebellar neurons (11) and in PC12 cells treated with nerve growth factor (NGF) or basic fibroblast growth factor (bFGF) (12, 13). Increases in neurite length could disturb neuronal function by delaying nerve conduction and by interfering with remodeling of neurites and synapses during development and learning.We have used PC12 cells as a model system to study mechanisms by which ethanol alters neurite outgrowth. We previously reported that enhancement of NGF-induced neurite outgrowth by ethanol was inhibited by downregulation of ,B, 6, and s isoforms of protein kinase C (PKC) (14). We also found that exposure to 25-100 mM ethanol for 2-6 days increased levels of mRNA (15) and protein (16) for 8 and s PKC and activated PKC in PC12 cells (16). Taken together, these findings suggest that ethanol enhances neurite formation by activating specific isozymes of PKC.One mechanism by which ethanol and PKC could modulate NGF-induced neurite outgrowth is by altering NGF signal transduction. A k...