Activation of metabotropic glutamate 4 receptors decreases L-DOPA-induced dyskinesia in a mouse model of Parkinson's disease.
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.
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Sébastien
S
Lopez
Alessandra
A
Bonito-Oliva
Simone
S
Pallottino
Francine
F
Acher
Gilberto
G
Fisone
D018663:Adrenergic Agents / Q000633:toxicity; D000613:Aminobutyrates / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D001545:Benserazide / Q000627:therapeutic use; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy / Q000378:metabolism*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects*; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy / Q000209:etiology; D010721:Phosphinic Acids / Q000494:pharmacology / Q000627:therapeutic use; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013997:Time Factors
D018663:Adrenergic Agents; D000613:Aminobutyrates; D000978:Antiparkinson Agents; D018690:Excitatory Amino Acid Agonists; C555637:LSP1 2111; D010721:Phosphinic Acids; D018094:Receptors, Metabotropic Glutamate; D007980:Levodopa; D001545:Benserazide; D016627:Oxidopamine; C108823:metabotropic glutamate receptor 4