Adenosine A(2A) Receptors in Striatal Glutamatergic Terminals and GABAergic Neurons Oppositely Modulate Psychostimulant Action and DARPP-32 Phosphorylation

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.