Dopamine D1 receptor signalling in dyskinetic Parkinsonian rats revealed by fiber photometry using FRET-based biosensors

作者：Jace Jones-Tabah, Hanan Mohammad, Shadi Hadj-Youssef, Lucy E. H. Kim, Ryan Martin, Faïza Benaliouad, Jason C. Tanny, Paul B. S. Clarke, Terence E. Hébert · 发表于：Scientific Reports · 年份：2020 · DOI：10.1038/s41598-020-71121-8 · 被引用次数：31 · 研究领域：Parkinson's Disease Mechanisms and Treatments、Neurotransmitter Receptor Influence on Behavior、Neuroscience and Neuropharmacology Research

As with many G protein-coupled receptors (GPCRs), the signalling pathways regulated by the dopamine D1 receptor (D1R) are dynamic, cell type-specific, and can change in the face of disease or drug exposures. In striatal neurons, the D1R activates cAMP/protein kinase A (PKA) signalling. However, in Parkinson's disease (PD), alterations in this pathway lead to functional upregulation of extracellular regulated kinases 1/2 (ERK1/2), contributing to L-DOPA-induced dyskinesia (LID). In order to detect D1R activation in vivo and to study the progressive dysregulation of D1R signalling in PD and LID, we developed ratiometric fiber-photometry with Förster resonance energy transfer (FRET) biosensors and optically detected PKA and ERK1/2 signalling in freely moving rats. We show that in Parkinsonian animals, D1R signalling through PKA and ERK1/2 is sensitized, but that following chronic treatment with L-DOPA, these pathways become partially desensitized while concurrently D1R activation leads to greater induction of dyskinesia.