A2A‐D2 receptor–receptor interaction modulates gliotransmitter release from striatal astrocyte processes

Evidence for striatal A2A‐D2 heterodimers has led to a new perspective on molecular mechanisms involved in schizophrenia and Parkinson's disease. Despite the increasing recognition of astrocytes’ participation in neuropsychiatric disease vulnerability, involvement of striatal astrocytes in A2A and D2 receptor signal transmission has never been explored. Here, we investigated the presence of D2 and A2A receptors in isolated astrocyte processes prepared from adult rat striatum by confocal imaging; the effects of receptor activation were measured on the 4‐aminopyridine‐evoked release of glutamate from the processes. Confocal analysis showed that A2A and D2 receptors were co‐expressed on the same astrocyte processes. Evidence for A2A‐D2 receptor–receptor interactions was obtained by measuring the release of the gliotransmitter glutamate: D2 receptors inhibited the glutamate release, while activation of A2A receptors, per se ineffective, abolished the effect of D2 receptor activation. The synthetic D2 peptide VLRRRRKRVN corresponding to the receptor region involved in electrostatic interaction underlying A2A‐D2 heteromerization abolished the ability of the A2A receptor to antagonize the D2 receptor‐mediated effect. Together, the findings are consistent with heteromerization of native striatal astrocytic A2A‐D2 receptors that via allosteric receptor–receptor interactions could play a role in the control of striatal glutamatergic transmission. These new findings suggest possible new pathogenic mechanisms and/or therapeutic approaches to neuropsychiatric disorders. Despite increasing recognition of the participation of astrocytes in the vulnerability to neuropsychiatric diseases such as schizophrenia or Parkinson's disease, the involvement of striatal astrocytes in A2A and D2 receptor signal transmission has not been explored in depth. We here provide evidence for heterodimers of adenosine A2A and dopamine D2 receptors in the striatum. A2A‐D2 receptor‐receptor interaction modulated 4‐aminopyridine‐evoked glutamate release: A2A (per se ineffective) antagonized the D2‐mediated release inhibition; VLRRRRKRVN, the D2 region involved in A2A‐D2 heteromerization, abolished the A2A effect. Findings that native striatal astrocytic A2A‐D2 receptor‐receptor interaction control glutamate release may be relevant to better understand neuropsychiatric disorders involving dysregulation of glutamate transmission at striatal neuron‐astrocyte networks.