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 in the awake rat has been used to study the role of A2A/D2 receptor interactions in the striato-pallidal GABA pathway in a model of Parkinson Disease (PD).The A2A agonist CGS 21680 and/or the D2 like agonist quinpirole were perfused via reverse microdialysis into the DA denervated striatum and the effects on globus pallidus extracellular GABA levels were evaluated. Evidence was obtained that CGS 21680 alone in the DA denervated but not the control striatum produced a transient rise of globus pallidus GABA levels. Quinpirole perfused alone into the DA denervated striatum produced a marked reduction of GP GABA levels which was not only counteracted by coperfused CGS 21680 but even led to an enhancement of the GABA levels, which was larger than the rise of GP GABA levels seen with CGS 21680 alone. These results can be explained by the existence not only of antagonistic A2A/D2 interactions but also by the appearance of D2/A2A interactions increasing the A2A signaling at the level of the Adenylate cyclase. Such actions may diminish the therapeutic efficacy of l-dopa and D2 agonists. An hypothesis has been advanced that l-dopa induced dyskinesias may substantially be caused by changes in the balance of A2A/D2 heteromers vs. A2A homers expressed at the surface membrane where now A2A homomers will dominate with abnormal increases in A2A signaling. This will lead to stabilization of abnormal receptor mosaics (hetero-oligomers) formed by the l-dopa treatment in the striato-pallidal GABA neurons in the DA denervated striatum via excessive phosphorylation with formation of wrong engrams, leading to formation of abnormal motor programs causing the appearance of dyskinesias.