Genetic deletion of GPR88 enhances the locomotor response to L-DOPA in experimental parkinsonism while counteracting the induction of dyskinesia

Neuropharmacology. 2020 Jan 1;162:107829. doi: 10.1016/j.neuropharm.2019.107829. Epub 2019 Oct 24.

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.

Keywords: 6hydroxydopamine; Dyskinesia; GPR88; Glutamate release; Parkinsonism; Rotations; l-DOPA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Agents / toxicity
  • Animals
  • Antiparkinson Agents / pharmacology*
  • Cholinesterase Inhibitors / toxicity
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism*
  • Dopamine Plasma Membrane Transport Proteins / genetics
  • Dyskinesia, Drug-Induced / etiology
  • Dyskinesia, Drug-Induced / genetics*
  • Dyskinesia, Drug-Induced / metabolism
  • Dyskinesia, Drug-Induced / physiopathology
  • GABAergic Neurons
  • Glutamic Acid / metabolism
  • Levodopa / pharmacology*
  • Locomotion / drug effects*
  • Locomotion / genetics
  • Male
  • Medial Forebrain Bundle
  • Mice
  • Mice, Knockout
  • Movement / drug effects*
  • Neuronal Plasticity / genetics
  • Oxidopamine / toxicity
  • Parkinsonian Disorders / genetics*
  • Parkinsonian Disorders / metabolism
  • Parkinsonian Disorders / physiopathology
  • RNA, Messenger / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, G-Protein-Coupled / genetics*
  • Receptors, G-Protein-Coupled / physiology
  • Serotonin / metabolism
  • Tacrine / toxicity
  • Tremor

Substances

  • Adrenergic Agents
  • Antiparkinson Agents
  • Cholinesterase Inhibitors
  • Dopamine Plasma Membrane Transport Proteins
  • Gpr88 protein, mouse
  • RNA, Messenger
  • Receptors, G-Protein-Coupled
  • Serotonin
  • Glutamic Acid
  • Levodopa
  • Tacrine
  • Oxidopamine