Desensitization of A₁ adenosine receptors in rat cerebral cortex

Following the subcutaneous administration of R(-)N⁶-(2-phenylisopropyl)adenosine (600 nmol/kg/hr) to rats for 1 week using Alzet® mini-osmotic pumps, A₁ adenosine receptor functions were determined using [³H]DPCPX binding, [³⁶5]GTP(γ)S binding, and adenylyl cyclase assays. A₁ adenosine receptor binding and the inhibition of adenylyl cyclase activity by PIA was not altered in cerebrocortical membranes prepared from PIA-treated rats. However, there was a significant decrease in the A₁ adenosine receptor-mediated stimulation of [³⁵S]GTP(γ)S binding to cerebrocortical membranes prepared from PIA-treated rats (22.0% decrease in basal activity; 19.7% decrease in maximal activity). These results suggest that the desensitization of A₁ adenosine receptors following chronic administration involves agonist-induced uncoupling of the receptors from G proteins rather than alteration of A₁ adenosine receptor molecules. It is also suggested that the determination of stimulation of [³⁵S]GTP(γ)S binding to G proteins is a suitable tool in studying the receptor regulation including desensitization.