Antagonistic interaction between adenosine A_2A receptors and dopamine D₂ receptors in the ventral striopallidal system. Implications for the treatment of schizophrenia

Recent studies have shown the existence of a specific antagonistic interaction between adenosine A_2areceptors and dopamine D₂ receptors in the brain. This A_2a-D₂ interaction seems to be essential for the behavioural effects of adenosine agonists and antagonists, like caffeine. In the present study quantitative receptor autoradiography and brain microdialysis were combined to demonstrate a powerful antagonistic A_2a- D₂ interaction in the ventral striopallidal system. In the presence of the A_2a agonist (2-p-carboxyethyl)phenylamino-5′-N carboxamidoadenosine, dopamine exhibited a lower efficacy in displacing the radiolabelled D₂ receptor antagonist [¹²⁵I]iodosulpiride from the rat ventral striatum, specially in the nucleus accumbens. A tonic dopaminergic modulation of the striopallidal neurons from the ventral striopallidal system was demonstrated by a dual-probe approach, by infusing selective dopamine agonists and antagonists in the nucleus accumbens and by measuring dopamine extracellular levels in the nucleus accumbens and GABA extracellular levels in the nucleus accumbens and in the ipsilateral ventral pallidum. The infusion of (2-p-carboxyethyl)phenylamino-5′-N-carboxamidoadenosine in the nucleus accumbens induced the same postsynaptic changes as the D₂ antagonist raclopride, i.e. an increase in pallidal GABA extracellular levels, without changing those levels in the nucleus accumbens. Furthermore, the coinfusion in the nucleus accumbens of low concentrations of (2-p-carboxyethyl)phenylamino-5′-N-carboxamido-adenosine and raclopride, which were ineffective when administered alone, induced a significant increase in pallidal γ -aminobutyric acid extracellular levels. These results suggest that A_2aagonists, alone or in combination with D₂ antagonists, could be advantageous antischizophrenic drugs, as blockade of D₂ receptors in the ventral striopallidal system appears to be associated with the antipsychotic activity of neuroleptics but not with their extrapyramidal motor-side effects.