Parkinson’s disease (PD) is a progressive neurodegenerative disorder associated with the loss of dopaminergic nigrostriatal neurons. Nowadays, PD is recognized as one of the most common neurological disorders, affecting approximately 1% of individuals older than 60 years. Associated features and symptoms include resting tremor, rigidity, bradykinesia or postural instability, and latter on cognitive dysfunction and dementia. In PD, striatal dopamine is reduced producing an imbalance between direct and indirect pathways, thus altering the central role that the striatum plays in processes such as motor activity control, motor learning and some forms of associative and visual learning. Despite surgical interventions (i.e. deep brain stimulation) can be performed, PD treatment is primarily based on pharmacotherapy (i.e. L-DOPA). However, long term treatments tend to lose efficacy and also to induce severe collateral motor effects (dyskinesia and rigidity) and psychiatric problems. Nowadays, PD research is focused on seeking new pharmacological tools, not only to provide a better and more effective management of PD symptoms but also lowering the risk of dyskinesias, particularly for younger patients in which the development of LID is more likely. An interesting alternative to the direct dopaminergic intervention would consist of the indirect manipulation of the dopaminergic system through parallel neurotransmission systems. Indeed, the demonstration of molecular and functional interactions between GPCRs belonging to different neurotransmission modes (i.e. glutamate, dopamine and adenosine) has opened new pharmacological avenues for the treatment of neurodegenerative diseases in general and for PD in particular.
Indeed, we recently visualized for the first time the A2AR/D2R oligomer in native tissue, namely rat striatum. Importantly, we also demonstrated that the striatal A2AR/D2R oligomer is down-regulated in a PD animal model, thus suggesting the existence of a disease-mediated modulation of A2AR/D2R oligomeric state. Interestingly, in the same PD animal model, the A2AR showed constitutive activity and this uncontrolled A2AR activity was blocked by caffeine, thus uncovering the mechanism by which caffeine is postulated to be an antiparkinsonian compound. Overall, the existence of A2AR-containing oligomers opens new opportunities for pharmacological intervention, not only in PD but also in those neurological diseases where the adenosinergic system may play a role (i.e. schizophrenia).
The pharmacological treatment of schizophrenia is currently based on restoring striatal dopamine and prefrontal cortex glutamate neurotransmission. However, these therapies are usually insufficient to entirely manage all disease symptoms (i.e. negative and cognitive symptoms). Interestingly, adenosine, as a neuromodulator has been demonstrated to be able of modulating not only the dopaminergic but also glutamatergic system, thus representing a promising candidate to restore the schizophrenia associated dopamine-glutamate imbalance that may underlie the origins of the disease. Accordingly, the development of drugs targeting adenosine receptors would constitute a worthwhile challenge for current neuropharmacology, since these compounds would definitively enrich the pharmacological arsenal and the pharmacotherapeutic opportunities surrounding schizophrenia.
Additional reading:
Decreased striatal adenosine A2A-dopamine D2 receptor heteromerization in schizophrenia. (2021) Valle-León, M., Callado, L.F., Aso, E., Cajiao-Manrique, M.M., Sahlholm, K., López-Cano, M., Soler, C., Altafaj, X., Watanabe, M., Ferré, S., Fernández-Dueñas, V., Menchón, J.M. & Ciruela, F. Neuropsychopharmacology 46 (3), 665-672.
Striatal Dopamine D2-Muscarinic Acetylcholine M1 Receptor-Receptor Interaction in a Model of Movement Disorders. (2020) Crans, R.A.J., Wouters, E., Valle-León, M., Taura, J., Massari, C.M., Fernández-Dueñas, V., Stove, C.P. & Ciruela, F. Frontiers in Pharmacology 11, 194.
Control of glutamate release by complexes of adenosine and cannabinoid receptors. (2020) Köfalvi, A., Moreno, E., Cordomi, A., Cai, N-S., Fernández-Dueñas, V., Ferreira, S.G., Guixà-González, R., Sánchez-Soto, M., Yano, H., Casadó-Anguera, V., Cunha, R.A., Sebastião, A.M., Ciruela, F.*, Pardo, L.*, Casadó, V.*, Ferré, S.* BMC Biology 18 (1), 9.
Revealing Adenosine A2A-Dopamine D2 Receptor Heteromers in Parkinson's Disease Post-Mortem Brain through a New AlphaScreen-Based Assay. (2019) Fernández-Dueñas, V.*, Gómez-Soler, M.*, Valle-León, M.*, Watanabe, M., Ferrer, I. & Ciruela, F. International Journal of Molecular Sciences 20 (14), 3600.