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Genetic deletion of GPR88 enhances the locomotor response to L-DOPA in experimental parkinsonism while counteracting the induction of dyskinesia.
- Source :
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Neuropharmacology [Neuropharmacology] 2020 Jan 01; Vol. 162, pp. 107829. Date of Electronic Publication: 2019 Oct 24. - Publication Year :
- 2020
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Abstract
- Parkinson's disease (PD) is characterized by progressive loss of midbrain dopaminergic neurons and treated with the dopamine precursor, 3,4-dihydroxy-l-phenylalanine (L-DOPA). Prolonged L-DOPA treatment is however associated with waning efficacy and the induction of L-DOPA induced dyskinesia (LID). GPR88 is an orphan G-protein Coupled Receptor (GPCR) expressed in dopaminoceptive striatal medium spiny neurons (MSNs) and their afferent corticostriatal glutamatergic neurons. Here, we studied the role of GPR88 in experimental parkinsonism and LID. Chronic L-DOPA administration to male GPR88 KO mice, subjected to unilateral 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle, resulted in more rotations than in their WT counterparts. Conversely, GPR88 KO mice had a lower abnormal involuntary movements (AIMs) score. These behavioral responses were accompanied by altered transcription of L-DOPA upregulated genes in lesioned GPR88 KO compared to WT striata. In accordance with a role for serotonin neurons in LID development, WT but not GPR88 KO striata exhibited 5-hydroxytryptamine displacement upon repeated L-DOPA treatment. Intact male GPR88 KO mice showed diminished tacrine-induced PD-like tremor and spontaneous hyperlocomotion. Dopamine and its metabolites were not increased in male GPR88 KO mice, but biosensor recordings revealed increased spontaneous/basal and evoked glutamate release in striata of male GPR88 KO mice. In conclusion, genetic deletion of GPR88 promotes l-DOPA-induced rotation and spontaneous locomotion yet suppresses the induction of LIDs and also reduces tremor. These data provide behavioral, neurochemical and molecular support that GPR88 antagonism may favour motor relief in PD patients without aggravating the induction of motor side effects.<br /> (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Subjects :
- Adrenergic Agents toxicity
Animals
Cholinesterase Inhibitors toxicity
Corpus Striatum drug effects
Dopamine Plasma Membrane Transport Proteins genetics
Dyskinesia, Drug-Induced etiology
Dyskinesia, Drug-Induced metabolism
Dyskinesia, Drug-Induced physiopathology
GABAergic Neurons
Glutamic Acid metabolism
Locomotion genetics
Male
Medial Forebrain Bundle
Mice
Mice, Knockout
Neuronal Plasticity genetics
Oxidopamine toxicity
Parkinsonian Disorders metabolism
Parkinsonian Disorders physiopathology
RNA, Messenger drug effects
RNA, Messenger genetics
RNA, Messenger metabolism
Receptors, G-Protein-Coupled physiology
Serotonin metabolism
Tacrine toxicity
Tremor
Antiparkinson Agents pharmacology
Corpus Striatum metabolism
Dyskinesia, Drug-Induced genetics
Levodopa pharmacology
Locomotion drug effects
Movement drug effects
Parkinsonian Disorders genetics
Receptors, G-Protein-Coupled genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1873-7064
- Volume :
- 162
- Database :
- MEDLINE
- Journal :
- Neuropharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 31666199
- Full Text :
- https://doi.org/10.1016/j.neuropharm.2019.107829