Summary Long-term incubation of clonal neural cell lines with ethanol differentially reduces the stimulation of cAMP accumulation by hormones and cholera toxin. In the NG108-15 neuroblastoma x glioma hybrid cell line, this heterologous desensitization was associated with a 42% reduction in the expression of G sα and no significant change in G iα. By contrast, ethanol treatment of the parental neuroblastoma cell line N18TG2 caused little loss of response to hormones or cholera toxin and no significant change in G sα or G iα. Ethanol induced heterologous desensitization in N1E-115 neuroblastoma cells; however, this cell line showed a dose-dependent increase in G iα and a later decrease in G sα. Thus, ethanol causes heterologous desensitization of hormone-stimulated cAMP accumulation by different mechanisms in related neural cell lines.