Electrophysiological and behavioural evidence for an antagonistic modulatory role of adenosine A(2A) receptors in dopamine D-2 receptor regulation inthe rat dopamine-denervated striatum

It has been shown that striatal adenosine A(2A) receptors can antagonistica lly interact with dopamine D-2 receptors at the membrane level leading to a decrease in the affinity and efficacy of D-2 receptors. Extracellular reco rdings and rotational behaviour were employed to obtain a correlate to thes e findings in an animal model of Parkinson's disease (PD). The recordings w ere performed in rats with unilateral 6-hydroxydopamine (6-OHDA)-induced ca techolamine depletion. While recording in the dopamine-depleted striatum, l ocal applications of the dopamine D-2 agonist quinpirole reduced neuronal a ctivity. However, when the adenosine A(2A) antagonist MSX-3 was applied sim ultaneously with quinpirole, the inhibition of neuronal firing seen after q uinpirole alone was significantly potentiated (P < 0.001, n = 11). In contr ast, local application of CGS 21680 attenuated the effect of quinpirole. Th e doses of MSX-3 and CGS 21680 used to achieve the modulation of quinpirole action had no effect per se on striatal neuronal firing. Furthermore, rota tional behaviour revealed that MSX-3 dose-dependently increased the number of turns when administrated together with a threshold dose of quinpirole wh ile no enhancement was achieved when MSX-3 was combined with SKF 38393. MSX -3 alone did not induce rotational behaviour. In conclusion, this study sho ws that low ineffective doses of MSX-3 enhance the effect of quinpirole on striatal firing rate, while the A(2A) agonist exerts the opposite action. T his mechanism gives a therapeutic potential to A(2A) antagonists in the tre atment of PD by enhancing D-2 receptor function.