Loss of the preferential control over the striato-nigral direct pathway by striatal NMDA receptors in a rat model of Parkinson's disease

By using multi-probe microdialysis we previously demonstrated that endogenous glutamate differentially regulates the activity of the striatal output pathways in vivo, through N-methyl-D-aspartate (NMDA) receptors containing the GluN2A or GluN2B subunits. Using the same approach, we presently investigate whether reverse dialysis of NMDA in the striatum differentially affects GABA release in the striatum and in striatal target areas, i.e. globus pallidus (GP) and substantia nigra reticulata (SNr). Moreover, we ask whether this control is altered under parkinsonian conditions. Intrastriatal NMDA perfusion (10 min) evoked GABA release more potently in SNr (1–100 μM) than in other regions (10–100 μM), suggesting preferential control over striato-nigral projection neurons. Intrastriatal NMDA more potently stimulated glutamate levels in the striatum (1–100 μM) and SNr (1–10 μM) than in GP (10 μM). Striatal dopamine denervation with 6-hydroxydopamine caused a leftward shift in the NMDA concentration–response curve. Intrastriatal NMDA elevated GABA levels at 0.1 μM (all regions) and 1 μM (striatum and GP only), but not at higher concentrations, indicating that, compared to naïve animals, the GABA response in SNr was attenuated. Attenuation of the glutamate response was also observed in SNr (NMDA effective only at 0.1 μM). Conversely, the glutamate response in GP was widened (NMDA effective in the 0.1–1 μM range). We conclude that NMDA preferentially stimulates the activity of the striato-nigral direct pathway under physiological conditions. In Parkinson’s disease, dopamine loss compromises the NMDA ability to stimulate striato-nigral neurons, thus shifting the NMDA control towards the striato-pallidal ones.