Effect of free radicals on adenosine A 2A and dopamine D 2 receptors in the striatum of young adult and aged rats

Abstract

Parkinson’s disease (PD) is a prevalent age-related motor dysfunction resulting from the hyperactivity of the indirect striatal pathway, which is controlled in an antagonistic manner by inhibitory dopamine D 2 and facilitatory adenosine A 2A receptors. Thus, dopamine precursors like l-DOPA are the standard therapy and A 2A antagonists are now tested as anti-parkinsonians. Increased free radicals levels occur on aging and are proposed to be a contributing factor for PD. We now tested if free radicals affected A 2A and D 2 receptors in striatal membranes of young adult (2 months) and old (24 months) rats. The A 2A receptor antagonist [ 3 H ]SCH 58261 bound to striatal membranes with a K D of 0.9 nM and a B max of 953 fmol/mg protein in young rats and with a K D of 0.8 nM and a B max of 725 fmol/mg protein in aged rats (24% decrease). The D 2 receptor antagonist [ 3 H ]raclopride bound to striatal membranes with a K D of 4.0 nM and a B max of 598 fmol/mg protein in young rats and with a K D of 4.3 nM and a B max of 368 fmol/mg protein in aged rats (38% decrease). Exposure of striatal membranes to a free radical generation system (2 mM FeSO 4 and 4 mM ascorbate) caused a similar decrease of [ 3 H ]SCH 58261 (35%) and [ 3 H ]raclopride (37%) binding in young adult rats but caused a greater decrease of [ 3 H ]SCH 58261 (49%) than of [ 3 H ]raclopride (20%) binding in aged rats. Thus, in aged rats, there is an unbalance of A 2A/D 2 receptor density favouring A 2A receptors, which is restored on exposure to free radicals. This supports the hypothesis that the effectiveness of A 2A receptor antagonists as anti-parkinsonians, demonstrated in young adult animals, may not be affected by a modified A 2A/D 2 receptor density in aged individuals suffering from exposure to increased free radical levels, as occurs in PD.