A2A-D2 Receptor Heterodimerization and Psychosis

Neuroleptic drugs, classified in typical and atypical, mainly act as D2 dopamine receptor antagonists. D2 and A2A receptors are co-expressed in the striatum where they structurally interact to form functional heterodimers. It has been demonstrated these receptors show a positive or negative functional cross-talk in dependence on their relative expression levels. To clarify the reciprocal interactions between adenosine and dopaminergic system in physiological conditions, we investigated the regulation of A2A adenosine receptor induced by D2 receptor antagonists in PC12 cells co-expressing both receptors in native conditions and in CHO cells co-expressing both receptors at levels comparable to those reported in striatum. In PC12 we were able to detect both receptors in the monomeric and dimeric form. Moreover, after chronic treatment with the typical antipsychotic haloperidol our results showed an increase of affinity and density of A2A receptor compared with the control, while treatment with atypical antipsychotics risperidone and clozapine did not show any significant difference. Treatment with haloperidol and risperidone showed an uncoupling of A2A receptor to G proteins and a significant decrease of cAMP levels. Chronic treatment with clozapine did not show any difference also in the G protein coupling and cAMP levels. In CHO cells our data showed that acute and chronic treatment with haloperidol increased the A2A AR affinity and responsiveness whereas no effects were detected with the atypical drug, clozapine. Otherwise, risperidone, an atypical antipsychotic but with high affinity for D2 DR, after long treatment induced a significant decrease of A2A AR affinity and responsiveness. Our results ascertain that A2A receptors are modulated by typical antipsychotics and by risperidone which profile does not fully fit to the atypical antipsychotic profile and these effects depend on the receptor levels. Our data suggest adenosine system as an alternative target for pathologies characterized by dopamine system dysfunction. In the same way, since A2A receptors are involved in brain damage, individual control of antipsychotic therapy and the associated regulation of adenosine system, may represent an important goal to control neurodegenerative processes considered as an amplificatory loop in several psychiatric disorders.