Phosphodiesterase 10A signaling in L-DOPA-induced dyskinesias

Abstract

Pharmacotherapy of Parkinson's disease (PD) is mainly based on the dopamine precursor L-DOPA. However, long-term treatment with L-DOPA has been associated with unwanted side effects called L-DOPA-induced dyskinesias (LID). Compounds that interfere with cyclic nucleotides (cAMP/cGMP) availability, such as phosphodiesterase (PDE) inhibitors, are emerging as a promising anti-dyskinetic co-therapy. The main goal of this project is to determine neurophysiological measures of LID induced by PDE10A inhibition in the 6-OHDA-lesioned rat model of PD using large-scale multi-structure electrophysiological recordings. Based on previous results from our groups, we will test the central hypothesis that cyclic nucleotide manipulation can modulate oscillations at network-level that are linked to pathological brain states such as LID. Based on our mutual research interests, we will implement this research collaboration, conducting experiments based on our ongoing projects in animal models of PD. The Brazilian group has expertise in animal models of neurodegenerative diseases neuropharmacology, and neurochemical methods. Conversely, the Swedish team has developed a highly promising neurophysiological approach for the development of new anti-dyskinetic therapies. Together, both groups will join power to consolidate a new approach to study PD and LID. The clinical implications of this discovery are expected to advance the treatment options for patients with PD. (AU)