Abstract
Extensive damage to nigrostriatal dopaminergic neurons leads to Parkinson’s disease (PD). To date, the most effective treatment has been administration of levodopa (L-DOPA) to increase dopaminergic tone. This treatment leads to responses that vary widely among patients, from predominantly beneficial effects to the induction of disabling, abnormal movements (L-DOPA induced dyskinesia (LID)). Similarly, experimental studies have shown animals with widely different degrees of LID severity. In this study, unilateral injections of 6-hydroxydopamine (6-OHDA) in the medial forebrain bundle (MFB) produced more than 90% depletion of dopamine in both the striatum and the substantia nigra reticulata (SNr) of rats. Population analysis showed that dopamine depletion levels were clustered in a single population. In contrast, analysis of abnormal involuntary movements (AIMs) induced by L-DOPA treatment of 6-OHDA-lesioned animals yielded two populations: one with mild LID, and the other with severe LID, which are also related to different therapeutic responses. We examined whether the severity of LID correlated with changes in dopamine 3 receptor (D3R) signaling because of the following: (a) D3R expression and the induction of LID are strongly correlated; and (b) dopaminergic denervation induces a qualitative change in D3R signaling in the SNr. We found that the effects of D3R activation on cAMP accumulation and depolarization-induced [3H]-gamma-aminobutyric acid ([3H]-GABA) release were switched. L-DOPA treatment normalized the denervation-induced changes in animals with mild LID. The D3R activation caused depression of both dopamine 1 receptor (D1R)-induced increases in cAMP production and depolarization-induced [3H]-GABA release, which were reversed to their pre-denervation state. In animals with severe LID, none of the denervation-induced changes were reversed. The finding that in the absence of identifiable differences in 6-OHDA and L-DOPA treatment, two populations of animals with different D3R signaling and LIDs severity implies that mechanisms intrinsic to the treated subject determine the segregation.
Highlights
Because extensive damage to the dopamine-producing neurons of the substantia nigra pars compacta (SNc) causes Parkinson’s disease (PD), the preferred therapeutic strategies for this conditionBiomolecules 2019, 9, 431; doi:10.3390/biom9090431 www.mdpi.com/journal/biomoleculesBiomolecules 2019, 9, 431 are based on substituting or increasing cerebral levels of the deficient neurotransmitter
In a group of 60 denervated rats, we compared changes in dopamine content between control and 6-OHDA-treated sides to quantify the impact of the damage to dopaminergic structures in the striatum and the substantia nigra reticulata (SNr) after 21 days of lesioning with our method
Since the qualitative differences between the two populations are generated by the same treatment schedule, it is very likely that the difference in LID severity is linked to the different expression of molecular mechanisms rather than to differences in the treatment protocol, which is in concordance with previous studies [48]
Summary
Biomolecules 2019, 9, 431 are based on substituting or increasing cerebral levels of the deficient neurotransmitter. In this regard, there is general agreement that the most effective treatment is the administration of the dopamine precursor levodopa (L-DOPA) [1]. The speed of the development and intensity of LID is determined by external causes observed in animal models (for a review, see Sharma et al [14]), such as degree of damage to dopaminergic neurons [15], age at onset of PD [16], duration of treatment [16,17], dosage [15], and frequency of L-DOPA treatment [18]. It has been stressed that intrinsic genetic features of the parkinsonian subject may determine LID development [19]
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