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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.

ABSTRACT: The loss of dopamine neurons combined or not with the subsequent administration of 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 substantia nigra, pars reticulate (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.

SUBMITTER: Wang H

PROVIDER: S-EPMC1894759 | biostudies-literature | 2007 Mar

REPOSITORIES: biostudies-literature

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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.

Wang H H Katz J J Dagostino P P Soghomonian J-J JJ

Neuroscience 20070109 2

The loss of dopamine neurons combined or not with the subsequent administration of 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 ...[more]

PMID: 17218060

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Project description:The substantia nigra pars reticulata (SNr), where the basal ganglia (BG) direct and indirect pathways converge, contains among the highest expression of cannabinoid receptor type 1 (CB1r) in the brain. Hence, SNr is an ideal locus to study pathway interactions and cannabinergic modulations. The objective of this study was to characterize the effects of systemic injections of the CB1r agonist (CP55940) on the balanced activity of the direct/indirect pathways in the SNr and its associated behaviors. To this aim, we recorded somatosensory and pathway-specific representations in the spiking activity of the SNr of male rats under CP55940. CB1r activation mainly decreased the inhibitory, potentially direct pathway component while sparing the excitatory, potentially indirect pathway component of somatosensory responses. As a result, cutaneous stimulation produced unbalanced responses favoring increased SNr firing rates, suggesting a potential locus for cannabinergic motor-related effects. To test this hypothesis, we implemented an ad hoc behavioral protocol for rats in which systemic administration of CP55940 produced kinematic impairments that were completely reverted by nigral injections of the CB1r antagonist (AM251). Our data suggest that cannabinoid-related motor effects are associated with unbalanced direct/indirect pathway activations that may be reverted by CB1r manipulation at the SNr.SIGNIFICANCE STATEMENT The cannabinergic system has been the target of multiple studies to master its potential use as a therapeutic agent. However, significant advances have been precluded by the lack of mechanistic explanations for the variety of its desirable/undesirable effects. Here, we have combined electrophysiological recordings, pharmacological and optogenetic manipulations, and an ad hoc behavioral protocol to understand how basal ganglia (BG) is affected by cannabinoids. We found that cannabinoids principally affect inhibitory inputs, potentially from the direct pathway, resulting in unbalanced responses in the substantia nigra pars reticulata (SNr) and suggesting a mechanism for the cannabinoid-related slowness of movements. This possibility was confirmed by behavioral experiments in which cannabinoid-related slowness of purposeful movements was reverted by cannabinoid receptor type 1 (CB1r) manipulations directly into the SNr.

Dataset Information

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.

Publications

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.

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