Rescue of locomotor impairment in dopamine D2 receptor-deficient mice by an adenosine A2A receptor antagonist

In Parkinson's disease a degeneration of dopaminergic neurons of the nigros triatal pathway is observed. Loss of dopaminergic regulation of striatal ne uron activity results in altered motor functions. Adenosine A2A (A2AR) and dopamine D2 (D2R) receptors are colocalized in striatal medium spiny neuron s. It has been proposed that adenosine binding to A2AR lowers the affinity of dopamine for D2R, thus modulating the function of this receptor. Absence of D2R in knockout mice (D2R-/-) results in impaired locomotion and coordi nated movements. This indicates that absence of dopamine in Parkinson's dis ease might principally affect D2R-mediated effects with regard to locomotor functions. A2AR-selective antagonists have been demonstrated to have antip arkinsonian activities in various models of Parkinson's disease in rodents and nonhuman primates. In this article, D2R-/- mice were used to explore th e possibility that an A2AR antagonist might reestablish their motor impairm ent. Interestingly, blockade of A2AR rescues the behavioral parameters alte red in D2R-/- mice. In addition, the level of expression of enkephalin and substance P, which were altered in D2R-/-, were also reestablished to norma l levels after A2AR antagonist treatment. These results show that A2AR and D2R have antagonistic and independent activities in controlling neuronal an d motor functions in the basal ganglia. They also provide evidence that sel ective A2AR antagonists can exhibit their anti-parkinsonian activities thro ugh a nondopaminergic mechanism.