Boolean analysis shows a high proportion of dopamine D receptors interacting with adenosine A receptors in striatal medium spiny neurons of mouse and non-human primate models of Parkinson's disease.

The antagonistic effect of adenosine on dopaminergic transmission in the basal ganglia indirect motor control pathway is mediated by dopamine D (DR) and adenosine A (AR) receptors co-expressed on medium spiny striatal neurons. The pathway is unbalanced in Parkinson's disease (PD) and an AR blocker has been approved for use with levodopa in the therapy of the disease. However, it is not known whether the therapy is acting on individually expressed receptors or in receptors forming A-D receptor heteromers, whose functionality is unique. For two proteins prone to interact, a very recently developed technique, MolBoolean, allows to determine the number of proteins that are either non-interacting or interacting. After checking the feasibility of the technique and reliability of data in transfected cells and in striatal primary neurons, the Boolean analysis of receptors in the striatum of rats and monkeys showed a high percentage of D receptors interacting with the adenosine receptor, while, on the contrary, a significant proportion of A receptors do not interact with dopamine receptors. The number of interacting receptors increased when rats and monkeys were lesioned to become a PD model. The use of a tracer of the indirect pathway in monkeys confirmed that the data was restricted to the population of striatal neurons projecting to the GPe. The results are not only relevant for being the first study quantifying individual versus interacting G protein-coupled receptors, but also for showing that the DR in these specific neurons, in both control and PD animals, is under the control of the AR. The tight adenosine/dopamine receptor coupling suggest benefits of early antiparkinsonian treatment with adenosine receptor blockers.