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Adenosine A 2A  receptors (A 2A R) are located postsynaptically in striatopallidal GABAergic neurons, antagonizing dopamine D 2  receptor functions, and are also located presynaptically at corticostriatal terminals, facilitating glutamate release. To address the hypothesis that these two A 2A R populations differently control the action of psychostimulants, we characterized A 2A R modulation of cocaine-induced effects at the level of DARPP-32 phosphorylation at Thr-34 and Thr-75, c-Fos expression, and psychomotor activity using two lines of cell-type selective A 2A R knockout (KO) mice with selective A 2A R deletion in GABAergic neurons (striatum-A 2A R-KO mice), or with A 2A R deletion in both striatal GABAergic neurons and projecting cortical glutamatergic neurons (forebrain-A 2A R-KO mice). We demonstrated that striatum-A 2A R KO mice lacked A 2A Rs exclusively in striatal GABAergic terminals whereas forebrain-A 2A R KO mice lacked A 2A Rs in both striatal GABAergic and glutamatergic terminals leading to a blunted A 2A R-mediated facilitation of synaptosomal glutamate release. The inactivation of A 2A Rs in GABAergic neurons reduced striatal DARPP-32 phosphorylation at Thr-34 and increased its phosphorylation at Thr-75. Conversely, the additional deletion of corticostriatal glutamatergic A 2A Rs produced opposite effects on DARPP-32 phosphorylation at Thr-34 and Thr-75. This distinct modulation of DARPP-32 phosphorylation was associated with opposite responses to cocaine-induced striatal c-Fos expression and psychomotor activity in striatum-A 2A R KO (enhanced) and forebrain-A 2A R KO mice (reduced). Thus, A 2A Rs in glutamatergic corticostriatal terminals and in GABAergic striatal neurons modulate the action of psychostimulants and DARPP-32 phosphorylation in opposite ways. We conclude that A 2A Rs in glutamatergic terminals prominently control the action of psychostimulants and define a novel mechanism by which A 2A Rs fine-tune striatal activity by integrating GABAergic, dopaminergic and glutamatergic signaling.

plos one

Adenosine A2A Receptors in Striatal Glutamatergic Terminals and GABAergic Neurons Oppositely Modulate Psychostimulant Action and DARPP-32 Phosphorylation