Adenosine A(2A) receptors, dopamine D(2) receptors and their interactions in Parkinson's disease.

Future therapies in Parkinson's disease may substantially build on the existence of intra-membrane receptor-receptor interactions in DA receptor containing heteromeric receptor complexes. The A2A/D2 heteromer is of substantial interest in view of its specific location in cortico-striatal glutamate terminals and in striato-pallidal GABA neurons. Antagonistic A2A/D2 receptor interactions in this heteromer demonstrated at the cellular level, and at the level of the striato-pallidal GABA neuron and at the network level made it possible to suggest A2A antagonists as anti-parkinsonian drugs. The major mechanism is an enhancement of D2 signaling leading to attenuation of hypokinesia, tremor, and rigidity in models of Parkinson's disease with inspiring results in two clinical trials. Other interactions are antagonism at the level of the adenylyl cyclase; heterologous sensitization at the A2A activated adenylyl cyclase by persistent D2 activation and a compensatory up-regulation of A2A receptors in response to intermittent Levodopa treatment. An increased dominance of A2A homomers over D2 homomers and A2A/D2 heteromers after intermittent Levodopa treatment may therefore contribute to development of Levodopa induced dyskinesias and to the wearing off of the therapeutic actions of Levodopa giving additional therapeutic roles of A2A antagonists. Their neuroprotective actions may involve an increase in the retrograde trophic signaling in the nigro-striatal DA system.