Experimental studies and theoretical aspects on A2A/D2 receptor interactions in a model of Parkinson's disease. Relevance for L-dopa induced dyskinesias

Dual probe microdialysis was used to study A2A/D2 receptor interactions in the striato-pallidal GABA pathway in a model of Parkinson's Disease. The A2A agonist CGS21680 and/or the D2-like agonist quinpirole were perfused via reverse microdialysis into the DA denervated striatum and the effects on globus pallidus (GP) extracellular GABA levels were evaluated. CGS21680 alone produced in the DA denervated striatum a transient rise of GP GABA levels. Quinpirole perfused alone into the DA denervated striatum reduced GP GABA levels, which was not only counteracted by coperfused CGS21680, but led to an enhancement of the GABA levels, which was larger than that seen with CGS21680 alone. These results may reflect existence not only of antagonistic A2A/D2 interactions but also of the appearance of D2/A2A interactions increasing the A2A signaling at the level of the adenylate cyclase. Such actions diminish the therapeutic efficacy of L-dopa and D2 agonists. L-dopa induced dyskinesias could be caused by changes in the balance of A2A/D2 heteromers vs A2A homomers expressed at the surface membrane, where A2A homomers dominate with abnormal increases in A2A signaling. This may lead to stabilization of abnormal receptor mosaics (high order hetero-oligomers) leading to formation of abnormal motor programs contributing to dyskinesia development.