Affiliations: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden | Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS-Université Paris Descartes, Paris, France
Note:  Present address: Rutgers University, Center for Molecular and Behavioral Neuroscience, Newark, NJ, USA.
Note:  Correspondence to: Gilberto Fisone, Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 171 77 Stockholm, Sweden. Tel.: +46 8 52487375; Fax: +46 8 320988; E-mail: [email protected]
Abstract: Group III metabotropic glutamate (mGlu) receptors modulate glutamatergic and GABAergic transmission in the basal ganglia. In this study, we examined a novel orthosteric agonist at the mGlu4 receptor, LSP1-2111, for its ability to affect L-DOPA-induced dyskinesia (LID), in a mouse model. In 6-OHDA-lesioned mice treated with L-DOPA, chronic co-administration of LSP1-2111 significantly attenuated the development of abnormal involuntary movements, which are regarded as a marker of dyskinesia. In contrast, a single injection of LSP1-2111 did not modify the expression of LID, once this condition had been established by previous administration of L-DOPA. LSP1-2111 did not affect L-DOPA-induced cAMP and extracellular signal-regulated protein kinase signaling, which have been previoulsy implicated in dyskinesia. These results indicate that co-administration of LSP1-2111 may improve the efficacy of standard L-DOPA therapy by attenuating its liability for dyskinesia.
Keywords: Basal ganglia, dyskinesia, group III metabotropic glutamate receptors, L-DOPA, LSP1-2111, mouse