Antagonistic interaction between adenosine A2A receptors and dopamine D2 receptors in the ventral striopallidal system. Implications for the treatment of schizophrenia.

Recent studies have shown the existence of a specific antagonistic interaction between adenosine A2a receptors and dopamine D2 receptors in the brain. This A2a-D2 interaction seems to be essential for the behavioural effects of adenosine agonists and antagonists, like caffeine. In the present study quantitative receptor autoradiography and brain microdialysis were combined to demonstrate a powerful antagonistic A2a-D2 interaction in the ventral striopallidal system.

A2a/D2 receptor interactions are not observed in COS-7 cells transiently transfected with dopamine D2 and adenosine A2a receptor cDNA.

The rat D2 receptor and the dog A2a receptor subcloned into the pXM vector were transiently transfected into COS-7 cells using the DEAE-dextran method. The transfected cells expressed approx. 200 fmol D2 receptors/mg protein and approx.

Chronic haloperidol treatment leads to an increase in the intramembrane interaction between adenosine A2 and dopamine D2 receptors in the neostriatum.

Stimulation of adenosine A2 receptors (with the selective adenosine A2 agonist CGS 21680) in rat striatal membrane preparations, produces a decrease in both the affinity of D2 receptors and the transduction of the signal from the D2 receptor to the G protein. This intramembrane A2-D2 interaction might be responsible for the behavioural depressant effects of adenosine agonists and for the behavioural stimulant effects of adenosine antagonists such as caffeine and theophylline. Dopamine denervation induces an increase in the intramembrane A2-D2 interaction, which may underlie the observed higher sensitivity to the behavioural effects induced by adenosine antagonists found in these animals.

Opposing actions of an adenosine A2 receptor agonist and a GTP analogue on the regulation of dopamine D2 receptors in rat neostriatal membranes.

We have previously found, in rat striatal membrane preparations, that stimulation of adenosine A2 receptors (with the selective adenosine A2 receptor agonist CGS 21680) increases the high- and low-affinity dissociation constants and increases the proportion of high-affinity dopamine D2 receptor binding sites labelled with the selective dopamine D2 receptor antagonist [3H]raclopride. As guanine nucleotides and divalent cations (such as Mg2+) are known to regulate the proportion of high-affinity D2 receptor binding sites in opposing ways, interaction experiments with CGS 21680, the GTP analogue Gpp(NH)p and MgCl2 were performed. Our results suggest that these three factors exert significant, though independent, effects on the proportion of high affinity D2 receptors, and that A2 receptors regulate both the affinity of D2 receptors and the transduction of the signal from the D2 receptor to the G-protein.