We used in vivo proton ((1)H) Magnetic Resonance Spectroscopy (MRS) to measure the levels of the main excitatory amino acid, glutamate (Glu) and also glutamine (Gln) and GABA in the striatum and cerebral cortex in the MPTP-intoxicated mouse, a model of dopaminergic denervation, before and after dopamine (DA) replacement. The study was performed at 9.4T on control mice (n = 8) and MPTP-intoxicated mice (n = 8). In vivo spectra were acquired in a voxel (8 microL) centered in the striatum, and in the cortex (4.6 microL). Three days after basal MRS acquisitions new spectra were acquired in the striatum and cortex, after levodopa (200 mg.kg(-1)). Glu, Gln and GABA concentrations obtained in the basal state were significantly increased in the striatum of MPTP-lesioned mice (Glu: 20.2 +/- 0.8 vs 11.4 +/- 0.9 mM, p < 0.001; Gln: 5.4 +/- 1.6 vs 2.0 +/- 0.6 mM, p < 0.05; GABA: 3.6 +/- 0.8 vs 1.6 +/- 0.2 mM, p < 0.05). Levodopa lowered metabolites concentrations in the striatum of MPTP-lesioned mice (Glu: 20.2 +/- 0.8 vs 11.2 +/- 0.4 mM (+ Ldopa), p < 0.001; Gln: 5.4 +/- 1.6 vs 1.6 +/- 0.4 mM (+ Ldopa), p < 0.05; GABA: 3.6 +/- 0.8 vs 1.7 +/- 0.4 mM (+ Ldopa), p < 0.01). Metabolite levels in the striatum of MPTP-intoxicated mice + levodopa were not significantly different from those in the striatum of controls. No change was found in the cortex after DA denervation and after DA replacement between the two animals groups. These results strongly support a predominant change in striatal Glu synaptic activity in the cortico-striatal pathway. Acute levodopa administration reverses the increase of metabolites in the striatum.