Striatal metabotropic glutamate receptor function following experimental parkinsonism and chronic levodopa treatment

Excessive activation of ionotropic glutamate receptors in the striatum contributes to the pathophysiology of motor symptoms in Parkinson's disease. Metabotropic glutamate (mGlu) receptors regulate striatal excitatory synaptic transmission, and adaptive changes in their function might occur following dopaminergic denervation and chronic levodopa-treatment (L-DOPA). Corticostriatal glutamatergic transmission was examined in striatal slices obtained from rats unilaterally denervated with the dopaminergic neurotoxin, 6-hydroxy dopamine (6-OHDA), and from denervated rats chronically treated with L-DOPA plus benserazide (25 + 6.25 mg/kg, intraperitoneally, twice daily for 21 days). Selective agonists of mGlu2 and -3 receptor subtypes [compounds LY379268 and (2S,2'R,3'R)-2-(2',3'-[(3)H]-dicarboxycyclopropyl)glycine ([(3)H]DCG-IV)] exhibited a much greater potency in depressing excitatory transmission and corticostriatal synapses in slices prepared from 6-OHDA-lesioned animals. Dopaminergic denervation affected neither the ability of L-(+)-2-amino-4-phosphonobutyric acid (L-AP4; a selective agonist of mGlu4, -6, -7 and -8 receptors) to inhibit corticostriatal transmission, nor the ability of (S)-3,5-dihydroxyphenylglycine (3,5-DHPG; a selective agonist of mGlu1 and -5 receptors) to potentiate responses mediated by N-methyl-d-aspartate (NMDA) receptor activation in striatal neurones. The increased responsiveness to mGlu2/3 receptor agonists was no longer detected in slices from 6-OHDA-lesioned animals chronically treated with L-DOPA. 6-OHDA-induced denervation also led to an increased expression of striatal mGlu2/3 receptor proteins and to a >2-fold increase in the maximal density (B(max)) of [(3)H]DCG-IV binding sites. These increases were again reversed by chronic treatment with L-DOPA. No changes in the expression of mGlu4 receptors or the alpha(i1) and alpha(i2) subunits of the G(i) proteins were induced by any of the treatments. We suggest that an enhanced sensitivity of pre-synaptic inhibitory mGlu2/3 receptors might represent an adaptive change triggered by dopaminergic denervation, which can be reversed by L-DOPA treatment.