ADENOSINE RECEPTORS MEDIATE CELLULAR ADAPTATION TO ETHANOL IN NG108-15 CELLS

Acute ethanol treatment of NG108-15 neuroblastoma x glioma hybrid cell s results in inhibition of adenosine uptake with consequent increases in extracellular adenosine and intracellular cAMP concentrations. Chro nic exposure to ethanol, however, causes heterologous desensitization of receptors coupled to adenylyl cyclase via stimulatory guanine nucle otide regulatory protein. This heterologous desensitization is correla ted with a decrease in the amount of protein and mRNA for the GTP-bind ing subunit of stimulatory guanine nucleotide regulatory protein. In a ddition, after chronic exposure to ethanol, the adenosine transporter becomes tolerant to acute ethanol inhibition of adenosine uptake, and there is no longer an increase in extracellular adenosine. We have pre viously shown that extracellular adenosine is required for the develop ment of ethanol-induced heterologous desensitization. To examine the r ole of adenosine receptors in mediating these responses to ethanol, we used BW A1434U, an adenosine receptor antagonist that does not inhibi t nucleoside transport. BW A1434U caused f(-)-N-6-(R-phenyl-isopropyl) -adenosine-stimulated cAMP production in NG108-15 cells. BW A1434U als o completely blocked acute ethanol-induced increases in intracellular cAMP levels and prevented the development of ethanol-induced heterolog ous desensitization and the reduction in the GTP-binding subunit of st imulatory guanine nucleotide regulatory protein. In addition, BW A1434 U prevented the development of tolerance to ethanol-induced inhibition of adenosine transport. Our results indicate that in NG108-15 cells, adenosine receptors mediate ethanol-induced changed in cAMP signal tra nsduction and adenosine transport and that an adenosine receptor antag onist can block both these acute and chronic affects of ethanol.