Adenosine A_2A receptors modulate the dopamine D₂ receptor-mediated inhibition of synaptic transmission in the mouse...

Prefrontal cortex (PFC) circuits are modulated by dopamine acting on D₁ - and D₂ -like receptors, which are pharmacologically exploited to manage neuropsychiatric conditions. Adenosine A_2A receptors (A_2A R) also control PFC-related responses and A_2A R antagonists are potential anti-psychotic drugs. As tight antagonistic A_2A R-D₂ R and synergistic A_2A R-D₁ R interactions occur in other brain regions, we now investigated the crosstalk between A_2A R and D₁ /D₂ R controlling synaptic transmission between layers II/III and V in mouse PFC coronal slices. Dopamine decreased synaptic transmission, a presynaptic effect based on the parallel increase in paired-pulse responses. Dopamine inhibition was prevented by the D₂ R-like antagonist sulpiride but not by the D₁ R antagonist SCH23390 and was mimicked by the D₂ R agonist sumanirole, but not by the agonists of either D₄ R (A-412997) or D₃ R (PD128907). Dopamine inhibition was prevented by the A_2A R antagonist, SCH58261, and attenuated in A_2A R knockout mice. Accordingly, triple-labelling immunocytochemistry experiments revealed the co-localization of A_2A R and D₂ R immunoreactivity in glutamatergic (vGluT1-positive) nerve terminals of the PFC. This reported positive A_2A R-D₂ R interaction controlling PFC synaptic transmission provides a mechanistic justification for the anti-psychotic potential of A_2A R antagonists.