DOPAMINE DENERVATION LEADS TO AN INCREASE IN THE INTRAMEMBRANE INTERACTION BETWEEN ADENOSINE-A2 AND DOPAMINE-D2 RECEPTORS IN THE NEOSTRIATUM

We have previously found, in striatal membrane preparations from young (2 months old) rats, that stimulation of adenosine A2 receptors (with the selective adenosine A2 agonist CGS 21680) increases the dissociation constants of high- (K(h)) and low-affinity (K(l) dopamine D2 binding sites (labelled with the selective dopamine D2 antagonist [H-3]raclopride) without changing the proportion of high affinity binding sites (R(h). In the present study in striatal preparations from adult (6 months old) rats, it was found that in addition to the increase in both K(h) and K(l) values, stimulation of adenosine A2 receptors is associated with an increase in R(h). These results suggest that, in the adult rat, adenosine A2 stimulation may inhibit the behavioural effects induced by dopamine D2 stimulation both by decreasing the affinity and the transduction of dopamine D2 receptors. We have also studied the intramembrane A2-D2 receptor interaction in an experimental model of Parkinson's disease, namely in rats with a unilateral 6-OH-dopamine-induced lesion of the nigro-striatal dopamine pathway. It was found that a unilateral dopamine denervation is associated with a higher density of striatal dopamine D2 receptors in the order of 20%, without any change in their affinity compared with the unlesioned neostriatum. Furthermore, the density (B(max) values) of dopamine D2 receptors in the contralateral neostriatum was significantly higher (about 20%) than in the striatum from naive animals. This finding suggests that an unilateral dopamine denervation also induces compensatory long-lasting changes of dopamine D2 receptors in the contralateral neostriatum. In addition to the heightened sensitivity to dopamine agonists, it is known that the dopamine denervated striatum is more sensitive to adenosine antagonists like methylxanthines. If the adenosine A2-dopamine D2 interaction is the main mechanism of action mediating the central effects of methylxanthines, the dopamine denervation might also potentiate this interaction, i.e., dopamine D, receptors could be not only more sensitive to dopamine but also to adenosine A2 receptor activation. Our results support this hypothesis, since membrane preparations from the denervated neostriatum are more sensitive to the effect of CGS 21680 on dopamine D2 receptors. Thus a low dose of CGS 21680 (3 nM), which is not effective in membrane preparations from the neostriatum of naive animals, is still effective in membranes from the denervated neostriatum. These results underline the potential antiparkinsonian activity of adenosine A2 antagonists.