Desensitization of adenosine and dopamine receptors in rat brain after treatment with adenosine analogs

Maximally tolerated doses of N⁶-[(R)-1-methyl-2-phenylethyl]adenosine (0.50 nmol/hr/2 wk), 5'-N-ethylcarboxamide adenosine (NECA, 0.04 nmol/hr/2 wk) or deoxycoformycin (5 nmol/hr/1 wk) were administered i.c.v. to rats using miniosmotic pumps. Adenosine receptor function was subsequently assayed using both ligand binding and adenylate cyclase assays. Binding to A₁ receptors was quantitated using [³H]N⁶-[(R)-1-methyl-2-phenylethyl]adenosine, a selective agonist ligand at A₁ receptors. Differences in the binding of this ligand and that of [³H]NECA, which binds to A₁ and A₂ receptors with similar affinities, were used to quantitate A₂ receptors. None of the treatments affected A₁ receptor function as assessed by both ligand binding and adenylate cyclase assays. A₂ receptor binding and A₂ receptor-mediated stimulation of adenylate cyclase were blunted in striatal membranes from NECA- and deoxycoformycin-treated rats but unaffected in striatal membranes from N⁶-[(R)-1-methyl-2-phenylethyl]adenosine-treated rats. All three pretreatments attenuated D₁ dopamine receptor-mediated stimulation of adenylate cyclase in striatal membranes. These results suggest that 1) the A₂ adenosine receptor system is susceptible to desensitization and 2) different mechanisms are involved in the NECA- and deoxycoformycin-induced densensitization of A₂ adenosine receptor and D₁ dopamine receptor systems. It is suggested that the D₁ dopamine receptor desensitization is, in fact, due to the tonic stimulation of adenosine A₁ receptors.