We have found that ethanol-induced increases in extracellular adenosine activate adenosine receptors which, in turn, mediate many of the acute and chronic effects of ethanol in the nervous system. Several laboratories have demonstrated the importance of adenosine in mediating the acute and chronic effects of ethanol at multiple levels of investigation in the nervous system. These include genetic selection for ethanol sensitivity in mice, behavioral responses to ethanol in naive and tolerant animals, neurophysiologic responses in hippocampal slices, and at the level of cAMP signal transduction and gene expression in cultured neural cells. In this review we present results from our laboratory which document the role of adenosine in mediating ethanol-induced changes in neural function at a cellular and molecular level. A schematic summary of our findings is: Etoh-->decreases Ado uptake-->increases Extracellular Ado-->Activation of Adenosine A2 receptor-->increases cAMP-->increases PKA-->-->-->Heterologous Desensitization (decreases cAMP)-->-->-->insensitivity of adenosine uptake to ETOH