title: mGlu5, Dopamine D2 and Adenosine A2A Receptors in L-DOPA-induced Dyskinesias.
abstract: Patients with Parkinson's disease (PD) receiving L-3,4-dihydroxyphenylalanine (L-DOPA, the gold-standard treatment for this disease) frequently develop abnormal involuntary movements, termed L-DOPA-induced dyskinesias (LID). Glutamate overactivity is well documented in PD and LID. An approach to manage LID is to add to L-DOPA specific agents to reduce dyskinesias such as metabotropic glutamate receptor (mGlu receptor) drugs. This article reviews the contribution of mGlu type 5 (mGlu5) receptors in animal models of PD. Several mGlu5 negative allosteric modulators acutely attenuate LID in 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) monkeys and 6-hydroxydopamine(6-OHDA)-lesioned rats. Chronic administration of mGlu5 negative allosteric modulators to MPTP monkeys and 6-OHDA rats also attenuates LID while maintaining the antiparkinsonian effect of L-DOPA. Radioligand autoradiography shows an elevation of striatal mGlu5 receptors of dyskinetic L-DOPA-treated MPTP monkeys but not in those without LID. The brain molecular correlates of the long-term effect of mGlu5 negative allosteric modulators treatments with L-DOPA attenuating development of LID was shown to extend beyond mGlu5 receptors with normalization of glutamate activity in the basal ganglia of L-DOPA-induced changes of NMDA, AMPA, mGlu2/3 receptors and VGlut2 transporter. In the basal ganglia, mGlu5 receptor negative allosteric modulators also normalize the L-DOPA-induced changes of dopamine D2receptors, their associated signaling proteins (ERK1/2 and Akt/GSK3β) and neuropeptides (preproenkephalin, preprodynorphin) as well as the adenosine A2A receptors expression. These results show in animal models of PD reduction of LID with mGlu5 negative allosteric modulation associated with normalization of glutamate, dopamine and adenosine receptors suggesting a functional link of these receptors in chronic treatment with L-DOPA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Morin
authors.forename: Marc
authors.initials: M
authors.lastname: Morissette
authors.forename: Laurent
authors.initials: L
authors.lastname: Grégoire
authors.affiliation: Neuroscience Research Unit, Centre de recherche du CHU de Québec, 2705 Laurier Boulevard, Quebec, Qc, Canada, G1V 4G2. therese.dipaolo@crchul.ulaval.ca.
authors.forename: Thérèse
authors.initials: T
authors.lastname: Di Paolo
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology / Q000633:toxicity*; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism*; D006801:Humans; D007980:Levodopa / Q000494:pharmacology / Q000633:toxicity*; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*
chemical_list: D000978:Antiparkinson Agents; D043705:Receptor, Adenosine A2A; D064529:Receptor, Metabotropic Glutamate 5; D017448:Receptors, Dopamine D2; D007980:Levodopa