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

J Neurochem. 2004 Nov;91(4):873-80. doi: 10.1111/j.1471-4159.2004.02761.x.


Adenosine, by acting on adenosine A(1) and A(2A) receptors, exerts opposite modulatory roles on striatal extracellular levels of glutamate and dopamine, with activation of A(1) 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 A(1) and A(2A) receptors in glutamatergic nerve terminals. By using in vivo microdialysis techniques, local perfusion of NMDA (3, 10 microm), the selective A(2A) receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680; 3, 10 microm), the selective A(1) receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT; 300, 1000 microm), or the non-selective A(1)-A(2A) receptor antagonist in vitro caffeine (300, 1000 microm) 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 microm) counteracted dopamine release induced by NMDA, CGS 21680, CPT and caffeine. Co-perfusion with the selective A(2A) receptor antagonist MSX-3 (1 microm) 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 A(1) 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 A(1) vs. A(2A) receptor antagonism in the central effects of caffeine.

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / pharmacology
  • Adenosine A1 Receptor Antagonists
  • Adenosine A2 Receptor Agonists
  • Adenosine A2 Receptor Antagonists
  • Animals
  • Caffeine / pharmacology
  • Dopamine / analysis
  • Dopamine / metabolism*
  • Excitatory Amino Acid Agonists / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Glutamic Acid / metabolism*
  • Male
  • Microdialysis
  • N-Methylaspartate / pharmacology
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism*
  • Phenethylamines / pharmacology
  • Purinergic P1 Receptor Agonists
  • Purinergic P1 Receptor Antagonists
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Receptors, Purinergic P1 / metabolism*
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology*
  • Theophylline / analogs & derivatives*
  • Theophylline / pharmacology


  • Adenosine A1 Receptor Antagonists
  • Adenosine A2 Receptor Agonists
  • Adenosine A2 Receptor Antagonists
  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • Phenethylamines
  • Purinergic P1 Receptor Agonists
  • Purinergic P1 Receptor Antagonists
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Purinergic P1
  • 2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine
  • 8-cyclopentyl-1,3-dimethylxanthine
  • Caffeine
  • Glutamic Acid
  • N-Methylaspartate
  • Theophylline
  • Adenosine
  • Dopamine