Effects of Nigrostriatal Denervation and L-Dopa Therapy on the GABAergic Neurons of the Striatum in MPTP-treated Monkeys and Parkinson's Disease: AnIn SituHybridization Study of GAD₆₇mRNA

The effects of nigrostriatal denervation and L-dopa therapy on GABAergic neurons were analysed in patients with Parkinson's disease and in monkeys rendered parkinsonian by MPTP intoxication. The expression of the messenger RNA coding for the 67 kDa isoform of glutamic acid decarboxylase (GAD(67) mRNA), studied by quantitative in situ hybridization, was used as an index of the GABAergic activity of the striatal neurons. A significant increase in GAD(67) mRNA expression, generalized to all GABAergic neurons, was observed in MPTP-treated monkeys compared to control monkeys in the putamen and caudate nucleus (+44 and +67% respectively), but not in the ventral striatum. L-Dopa therapy significantly reduced GAD(67) mRNA expression in the putamen and caudate nucleus to levels similar to those found in control monkeys. However, the return to normal of GAD(67) mRNA expression was not homogeneous across all neurons since it was followed by an increase of labelling in one subpopulation of GABAergic neurons and a decrease in another. These data suggest that in MPTP-treated monkeys the degeneration of nigrostriatal dopaminergic neurons results in a generalized increase in GABAergic activity in all the GABAergic neurons of the striatum, which is partially reversed by L-dopa therapy. As the expression of GAD(67) mRNA is less intense in the ventral than in the dorsal striatum, this increase in striatal GABAergic activity may be related to the severity of nigrostriatal denervation. In parkinsonian patients who had been chronically treated with L-dopa, GAD(67) mRNA expression was significantly decreased in all GABAergic neurons, in the caudate nucleus (by 44%), putamen (by 43.5%) and ventral striatum (by 26%). The opposite variation of GAD(67) mRNA in patients with Parkinson's disease, compared with MPTP-treated monkeys, might be explained by the combination of chronic nigrostriatal denervation acid long-term L-dopa therapy.