Receptor crosstalk: haloperidol treatment enhances A2A adenosine receptor functioning in a transfected cell model

A 2A adenosine receptors are considered an excellent target for drug development in several neurological and psychiatric disorders. It is noteworthy that the responses evoked by A 2A adenosine receptors are regulated by D 2 dopamine receptor ligands. These two receptors are co-expressed at the level of the basal ganglia and interact to form functional heterodimers. In this context, possible changes in A 2A adenosine receptor functional responses caused by the chronic blockade/activation of D 2 dopamine receptors should be considered to optimise the therapeutic effectiveness of dopaminergic agents and to reduce any possible side effects. In the present paper, we investigated the regulation of A 2A adenosine receptors induced by antipsychotic drugs, commonly acting as D 2 dopamine receptor antagonists, in a cellular model co-expressing both A 2A and D 2 receptors. Our data suggest that the treatment of cells with the classical antipsychotic haloperidol increased both the affinity and responsiveness of the A 2A receptor and also affected the degree of A 2A –D 2 receptor heterodimerisation. In contrast, an atypical antipsychotic, clozapine, had no effect on A 2A adenosine receptor parameters, suggesting that the two classes of drugs have different effects on adenosine–dopamine receptor interaction. Modifications to A 2A adenosine receptors may play a significant role in determining cerebral adenosine effects during the chronic administration of antipsychotics in psychiatric diseases and may account for the efficacy of A 2A adenosine receptor ligands in pathologies associated with dopaminergic system dysfunction.