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 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.