Desensitization of adenosine A 2 receptors in the striatum of the rat following chronic treatment with diazepam

Abstract

Following prolonged treatment (7 days) with diazepam (10 mg/kg/day, using ALZET mini-osmotic pumps) in rats, the function of adenosine receptors was assessed in specific structures of the brain, using both agonist ligand binding and adenylate cyclase assays. Binding to A 1 receptors was quantitified using [ 3 H]N 6-[( R)-1- methyl-2- phenylethyl] adenosine, a selective ligand at A 1 receptors. Differences in the binding of this ligand and that of [ 3 H]5'-N- ethylcarboxamide adenosine, which binds to both A 1 and A 2 subtypes of receptors with similar affinities, were used to quantify A 2 receptors. Treatment with diazepam failed to alter the binding of [ 3 H]-N 6-[( R)-1- methyl-2- phenylethyl] adenosine in all areas of the brain studied. However, the binding of A 2 receptors and A 2 receptor-mediated stimulation of adenylate-cyclase were significantly attenuated in striatal membranes from diazepam-treated rats. Thus, the present study indicated that functional adenosine A 2 receptors were desensitized after prolonged treatment with diazepam, since decreased agonist binding to A 2 receptors paralleled an attenuation in the stimulation by adenosine of the activity of adenylate cyclase, an effect mediated by the A 2 receptor. These results further indicate that the changes in adenosine A 2 receptors correlated with significant short-lasting alterations in the sleep-wake cycle during the withdrawal of diazepam. The alterations in sleep-wakefulness did not correlate with the effect of diazepam on benzodiazepine receptors since no changes were observed in the binding of benzodiazepine receptors.