The Role of Adenosine and Adenosine Transport in Ethanol‐Induced Cellular Tolerance and Dependence

Abstract

Acute exposure to ethanol in culture inhibits adenosine uptake into cells, thereby increasing the concentration of extracellular adenosine. Extracellular adenosine then reacts with adenosine A2 receptors to stimulate intracellular cAMP production. During prolonged exposure to ethanol, the increase in cAMP is followed by the development of heterologous desensitization of receptors coupled to adenylyl cyclase via Gs, the stimulatory GTP-binding protein. Ethanol-induced heterologous desensitization appears to be due to a reduction in mRNA and protein for G alpha s, a subunit of Gs. This is an example of cellular dependence on ethanol. The important implication of these findings is that a selective inhibitory effect of ethanol on adenosine uptake can lead to desensitization of diverse receptors coupled to cAMP production. Such changes could contribute to the pleiotropic effects of ethanol in the brain and other organs. Prolonged exposure to ethanol also alters the nucleoside transport system. While ethanol inhibits adenosine uptake into naive cells, ethanol no longer inhibits adenosine uptake into cells that have adapted to ethanol. This resistance to ethanol inhibition appears to be a form of cellular tolerance to ethanol. Thus, there appears to be a synergism between ethanol-induced heterologous desensitization of receptor-stimulated cAMP production (cellular dependence) and resistance to ethanol inhibition of adenosine uptake (cellular tolerance), because both lead to reduced intracellular levels of cAMP. Our studies on cAMP signal transduction in cell culture are directly relevant to the pathophysiology of human alcoholism. Heterologous desensitization of cAMP production is demonstrable in lymphocytes taken from actively drinking alcoholics; this measurement appears to be a biologic marker of active alcohol consumption. In addition, regulation of adenosine receptor-dependent cAMP production may be altered in patients at risk to develop alcoholism because of genetic factors. Thus, lymphocytes from alcoholics cultured many generations in the absence of ethanol show increased adenosine receptor-dependent cAMP production and increased sensitivity to ethanol-induced heterologous desensitization. These persistent phenotypic abnormalities in cell culture could be used as genetic markers for alcoholism. Studies are under way to test this possibility.

Adenosine Signaling in Striatal Circuits and Alcohol Use Disorders

“…In contrast, chronic ethanol exposure to cultured cells no longer increases extracellular adenosine levels. Furthermore, chronic exposure decreases type 1 equilibrative nucleoside transporter (ENT1) expression (Diamond et al, 1991). Specifically, mice lacking ENT1 present with reduced adenosine levels in the nucleus accumbens (NAc).…”

Increased brain uptake and oxidation of acetate in heavy drinkers

“…Acetaldehyde dehydrogenase quickly catalyzes the conversion of acetaldehyde to acetate, and alcohol-dependent individuals show elevated acetate up to 24 hours after the last drink (17). Acetate enters the tricarboxylic acid (TCA) cycle for oxidation via acetyl-CoA synthetase, and the process of oxidation generates adenosine (18)(19)(20)(21), which has sedating properties similar to those of ethanol (22)(23)(24). One may expect heavy drinkers to have long periods of time with elevated levels of adenosine in their tissues.…”

Effects of Benzodiazepines on Acute and Chronic Ethanol‐Induced Nociception in Rats

“…A number of studies have indicated the contribution of adenosine receptors to antinociception (DeLander and Wahl, 1988;Gungor et al, 1994;Holmgren et al, 1986;Sawynok and Sweeney, 1989), and at least one study has suggested that adenosinergic antinociception may be modulated by GABA, compounds (Sabetkasai and Zarrindast, 1993). Furthermore, adenosine receptors have been found to be important in the development of tolerance to ethanol (Coe et al, 1996;Diamond et al, 1991;Sapru et al, 1994). Calcium channel blockers have also been reported to produce antinociception (Hunt et al, 1996;Martin et al, 1996;Sawynok et al, 1990).…”