Parkinson’s Disease & Movement Disorders

Biography

Biography: Dasiel O. Borroto-Escuela

Abstract

Among a large number of behavioural studies on adenosine A1– Dopamine D1 receptor interactions a few examples may be given. Thus, the A1 receptor agonist CPA counteracted the D1 receptor agonist (SKF 38393)-induced grooming behavior and counteracted dyskinetic behavior in rabbits. In line with these results, the A1 receptor antagonist CPT enhanced the motor activating effects of the D1 agonist SKF 38393 in reserpinized mice and in rat models of Parkinson's disease (unilateral 6-OH-dopamine lesions of the nigrostriatal dopamine pathway). These behavioral results at the network level indicate the existence of antagonistic A1–D1 receptor interactions. The molecular basis of the antagonistic A1–D1 receptor interactions likely involves the existence of A1–D1 heteroreceptor complexes in the direct pathway. The A1–D1 heteroreceptor complexes may reflect a direct physical interaction without the involvement of an adapter protein, since specific BRET and FRET signals can be detected between fluorescent-tagged A1 and D1 receptors upon transient co-transfection in cell lines. Furthermore, In situ Proximity Ligation Assay clearly demonstrated that A1 and D1 receptors exist as heteroreceptor complexes in rat brain. Antagonistic A1-D1 interactions also exist at the level of the second messengers. These results suggest a role of A1 receptor agonists and antagonists in the treatment of Parkinson's disease with dysfunction of D1 receptor signaling via their actions on the A1–D1 heteroreceptor complexes located in the direct pathway. A1 agonists may e.g. reduce levodopa induced dyskinesias. It will be of substantial interest to know how the A1–D1 receptor interaction may regulate trophic mechanisms such as neurotrophic factors and neuronal differentiation