Nucleoside Transport and Ethanol-Induced Heterologous Desensitization

Abstract

Chronic ethanol exposure causes heterologous desensitization of cAMP production by receptors coupled to Gα_s, the GTP-binding subunit of G_s (Mochly-Rosen et al., 1988). This occurs in several cultured cell lines as well as in brains from rats chronically exposed to ethanol (Gordon et al., 1986; Nagy et al., 1989; Hoffman and Tabakoff, 1977). Moreover, freshly isolated circulating lymphocytes from alcoholics also show heterologous desensitization when compared to cells from non-drinking controls (Diamond et al., 1987), suggesting that alterations in cAMP production may be important in the pathophysiology of alcoholism. Our studies on the mechanism underlying the decrease in cAMP production indicate that ethanol inhibition of nucleoside transport is a requisite first step in ethanol-induced heterologous desensization. Inhibition of adenosine transport by ethanol results in an extracellular accumulation of adenosine. This adenosine binds to adenosine A₂ receptors causing an increase in intracellular cAMP levels which leads to a cascade of events resulting in heterologous desensitization of cAMP signal transduction (Nagy et al., 1989; Nagy et al., 1990).