Potential for antipsychotic and psychotomimetic effects of A2A receptor modulation

The discovery of antagonistic interactions between A2A adenosine receptors and D2 dopamine receptors in the ventral striatum suggested that A2A receptor activation might modulate the antipsychotic effects of dopamine receptor antagonists and could provide an opportunity for the development of A2A receptor agonists as novel antipsychotic drugs. However, there is limited evidence from preclinical and clinical studies that A2A receptor agonists can exert antipsychotic effects. Furthermore, it remains unclear whether A2A receptor agonists possess a sufficient safety margin or whether their potent hypotensive effects or extrapyramidal side effects would limit their therapeutic utility as antipsychotic agents. The interaction between A2A receptors and D2 receptors also raises the possibility that A2A receptor antagonists, which hold considerable promise as antiparkinsonian agents, may have dose-limiting psychotomimetic side effects. Preclinical studies using selective A2A receptor antagonists suggest that this class of compound has a low propensity to elicit psychotomimetic side effects or exacerbate those induced by D2 receptor agonists.