Adenosine receptor-mediated modulation of dopamine release in the nucleus accumbens depends on glutamate neurotransmission and N-methyl-D-aspartate receptor stimulation

Adenosine, by acting on adenosine A₁ and A_2A receptors, exerts opposite modulatory roles on striatal extracellular levels of glutamate and dopamine, with activation of A₁ inhibiting and activation of A_2A receptors stimulating glutamate and dopamine release. Adenosine-mediated modulation of striatal dopaminergic neurotransmission could be secondary to changes in glutamate neurotransmission, in view of evidence for a preferential colocalization of A₁ and A_2A receptors in glutamatergic nerve terminals. By using in vivo microdialysis techniques, local perfusion of NMDA (3, 10 μM), the selective A_2A receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5′-N- ethylcarboxamidoadenosine (CGS 21680; 3, 10 μM), the selective A₁ receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT; 300, 1000 μM), or the non-selective A₁-A_2A receptor antagonist in vitro caffeine (300, 1000 μM) elicited significant increases in extracellular levels of dopamine in the shell of the nucleus accumbens (NAc). Significant glutamate release was also observed with local perfusion of CGS 21680, CPT and caffeine, but not NMDA. Co-perfusion with the competitive NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (APV; 100 μM) counteracted dopamine release induced by NMDA, CGS 21680, CPT and caffeine. Co-perfusion with the selective A_2A receptor antagonist MSX-3 (1 μM) counteracted dopamine and glutamate release induced by CGS 21680, CPT and caffeine and did not modify dopamine release induced by NMDA. These results indicate that modulation of dopamine release in the shell of the NAc by A₁ and A_2A receptors is mostly secondary to their opposite modulatory role on glutamatergic neurotransmission and depends on stimulation of NMDA receptors. Furthermore, these results underscore the role of A₁ vs. A _2A receptor antagonism in the central effects of caffeine.