The effect of adrenalectomy on the expression of adenosine receptors and their mRNA in rat brain was examined using quantitative autoradiography and in situ hybridization. 1,3-[3H]Dipropyl-8-cyclopentylxanthine ([3H]DPCPX), a selective adenosine A1 receptor antagonist, and [3H]CGS 21680, a selective adenosine A(2A) receptor agonist, were used as radioligands. One week after adrenalectomy, the expression of mRNA for adenosine A1 receptors was significantly decreased, as was the number of binding sites for [H]DPCPX. These effects were significantly counteracted by replacement treatment with dexamethasone (1.5 mg/kg i.p., twice daily). Addition of GTP caused a similar increase of [3H]DPCPX binding in sham-operated rats, adrenalectomized rats and rats adrenalectomized and treated with dexamethasone. Moreover, no differences in displacement of [3H]DPCPX by the adenosine receptor agonist N6-(R-phenylisopropyl)adenosine were found among these groups. Adrenalectomy did not significantly affect the number of [3H]CGS 21680 binding sites in striatum or the mRNA encoding adenosine A(2A) receptors. No changes in the affinity of [3H]CGS 21680 for adenosine A(2A) receptors or in the potency of the adenosine receptor agonist 2-chloroadenosine to displace [3H]CGS 21680 were found. Dexamethasone treatment decreased cAMP formation induced by the nonselective adenosine agonist 5'-N-ethylcarboxamidoadenosine in Jurkat cells, which express adenosine A(2B) receptors, but did not alter it in PC-12 cells, which express mostly A(2A) receptors. The results suggest that endogenous corticosteroids positively regulate the expression of adenosine A1 receptors, at least partly at the transcriptional level. In contrast, corticosteroids do not regulate the expression of adenosine A(2A) receptors.