Adenosine A 2A receptors modulate the dopamine D 2 receptor‐mediated inhibition of synaptic transmission in the mouse prefrontal cortex

Prefrontal cortex ( PFC ) circuits are modulated by dopamine acting on D 1 ‐ and D 2 ‐like receptors, which are pharmacologically exploited to manage neuropsychiatric conditions. Adenosine A 2A receptors (A 2 A R ) also control PFC ‐related responses and A 2 A R antagonists are potential anti‐psychotic drugs. As tight antagonistic A 2 A R –D 2 R and synergistic A 2 A R –D 1 R interactions occur in other brain regions, we now investigated the crosstalk between A 2 A R and D 1 /D 2 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 D 2 R‐like antagonist sulpiride but not by the D 1 R antagonist SCH 23390 and was mimicked by the D 2 R agonist sumanirole, but not by the agonists of either D 4 R (A‐412997) or D 3 R ( PD 128907). Dopamine inhibition was prevented by the A 2 A R antagonist, SCH 58261, and attenuated in A 2 A R knockout mice. Accordingly, triple‐labelling immunocytochemistry experiments revealed the co‐localization of A 2 A R and D 2 R immunoreactivity in glutamatergic ( vG luT1‐positive) nerve terminals of the PFC . This reported positive A 2 A R –D 2 R interaction controlling PFC synaptic transmission provides a mechanistic justification for the anti‐psychotic potential of A 2 A R antagonists.