Repeated cocaine administration changes the function and subcellular distribution of adenosine A(1) receptor in the rat nucleus accumbens

Adenosine A(1) receptor (A(1)) protein and mRNA is increased in the nucleus accumbens following repeated cocaine treatment. In spite of this protein up-regulation, A(1) agonist-stimulated [S-35]GTPgammaS binding was attenuated in accumbens homogenates of rats withdrawn for 3 weeks from 1 week of daily cocaine injections. Cellular subfractionation revealed that the discrepancy between total A(1) protein and G protein coupling resulted from a smaller proportion of receptors in the plasma membrane. The decrease in functional receptor in the plasma membrane was further indicated by diminished formation of heteromeric receptor complex consisting of A(1) and dopamine D-1A receptors. To explore the functional significance of the altered distribution of A(1) receptors, at 3 weeks after discontinuing repeated cocaine or saline, animals were injected with cocaine and 45 min later the subcellular distribution of A(1) receptors quantified. Whereas a cocaine challenge in repeated saline-treated animals induced a marked increase in membrane localization of the A(1) receptor, the relative distribution of receptors in repeated cocaine rats was not affected by acute cocaine. These data suggest that the sorting and recycling of A(1) receptors is dysregulated in the nucleus accumbens as the consequence of repeated cocaine administration.