mGlu5, Dopamine D₂ and Adenosine A_2A Receptors in L-DOPA-induced Dyskinesias

Title:mGlu5, Dopamine D₂ and Adenosine A_2A Receptors in L-DOPA-induced Dyskinesias

Volume: 14 Issue: 5

Author(s): Nicolas Morin, Marc Morissette, Laurent Grégoire and Thérèse Di Paolo

Affiliation:

Keywords: Adenosine receptor, dopamine receptor, glutamate receptor, L-DOPA, L-DOPA-induced dyskinesias, MPEP, MPTP monkey model, Parkinson’s disease.

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 D₂ receptors, their associated signaling proteins (ERK1/2 and Akt/GSK3β) and neuropeptides (preproenkephalin, preprodynorphin) as well as the adenosine A_2A 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.

Cite this article as:

Morin Nicolas, Morissette Marc, Grégoire Laurent and Di Paolo Thérèse, mGlu5, Dopamine D₂ and Adenosine A_2A Receptors in L-DOPA-induced Dyskinesias, Current Neuropharmacology 2016; 14 (5) . https://dx.doi.org/10.2174/1570159X14666151201185652