Unilateral 6-hydroxydopamine lesion of dopamine neurons and subchronic l-DOPA administration in the adult rat alters the expression of the vesicular GABA transporter in different subsets of striatal neurons and in the substantia nigra pars reticulata

摘要

The loss of dopamine neurons combined or not with the subsequent administration of levodopa (l-DOPA) in patients with Parkinson’s disease or in experimental models of the disease results in altered GABAergic signaling throughout the basal ganglia, including the striatum and the substantia nigra, pars reticulata. However, the molecular mechanisms involved in altered GABA neurotransmission remain poorly understood. In order to be released from synaptic vesicles, newly synthesized GABA is transported from the cytosol into synaptic vesicles by a vesicular GABA transporter. The objective of this study was to examine the hypothesis that expression of the vesicular GABA transporter vGAT is altered in the unilateral 6-hydroxydopamine model of Parkinson’s disease. Our results provide evidence that a unilateral 6-hydroxydopamine lesion results in increased and decreased vGAT mRNA levels in striatopallidal and striatonigral neurons, respectively. These two subsets of neurons were identified by the co-expression or lack of co-expression of preproenkephalin, a marker of striatopallidal neurons, using double-labeling in situ hybridization histochemistry. Such changes occurred in the striatum ipsilateral to the 6-hydroxydopamine lesion and were paralleled by decreased vGAT protein levels in the SNr. On the other hand, the subchronic systemic administration of l-DOPA increased vGAT mRNA levels in preproenkephalin-negative neurons on the side ipsilateral and, to a lesser extent, the side contralateral to the 6-hydroxydopamine lesion. Systemic l-DOPA also increased vGAT protein levels in the ipsi- and contralateral SNr. As a whole, the results provide original evidence that vGAT expression is altered in the 6-hydroxydopamine model of Parkinson’s disease. They also suggest that the behavioral effects induced by a subchronic administration of l-DOPA to 6-hydroxydopamine-lesioned rats involve an increase in the vesicular release of GABA by striatonigral neurons.