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Article

Severity of Dyskinesia and D3R Signaling Changes Induced by L-DOPA Treatment of Hemiparkinsonian Rats Are Features Inherent to the Treated Subjects

1
Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México 07360, Mexico
2
Laboratorio de Medicina Genómica, Departamento de Genética, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Ciudad de México 14389, Mexico
3
Neurosciences Program Bloomington, Indiana University, Bloomington, IN 47405, USA
4
Department of Physiology, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA
*
Author to whom correspondence should be addressed.
Biomolecules 2019, 9(9), 431; https://doi.org/10.3390/biom9090431
Received: 18 July 2019 / Revised: 20 August 2019 / Accepted: 29 August 2019 / Published: 1 September 2019
(This article belongs to the Special Issue Dopamine Receptor in Health and Diseases)
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. View Full-Text
Keywords: dopamine 3 receptors; dopamine 1 receptors; parkinson’s disease; dyskinesia; basal ganglia; substantia nigra pars reticulata dopamine 3 receptors; dopamine 1 receptors; parkinson’s disease; dyskinesia; basal ganglia; substantia nigra pars reticulata
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MDPI and ACS Style

Albarrán-Bravo, S.; Ávalos-Fuentes, J.A.; Cortés, H.; Rodriguez-Sánchez, M.; Leyva-García, N.; Rangel-Barajas, C.; Erlij, D.; Florán, B. Severity of Dyskinesia and D3R Signaling Changes Induced by L-DOPA Treatment of Hemiparkinsonian Rats Are Features Inherent to the Treated Subjects. Biomolecules 2019, 9, 431. https://doi.org/10.3390/biom9090431

AMA Style

Albarrán-Bravo S, Ávalos-Fuentes JA, Cortés H, Rodriguez-Sánchez M, Leyva-García N, Rangel-Barajas C, Erlij D, Florán B. Severity of Dyskinesia and D3R Signaling Changes Induced by L-DOPA Treatment of Hemiparkinsonian Rats Are Features Inherent to the Treated Subjects. Biomolecules. 2019; 9(9):431. https://doi.org/10.3390/biom9090431

Chicago/Turabian Style

Albarrán-Bravo, Sacnité, José Arturo Ávalos-Fuentes, Hernán Cortés, Marina Rodriguez-Sánchez, Norberto Leyva-García, Claudia Rangel-Barajas, David Erlij, and Benjamín Florán. 2019. "Severity of Dyskinesia and D3R Signaling Changes Induced by L-DOPA Treatment of Hemiparkinsonian Rats Are Features Inherent to the Treated Subjects" Biomolecules 9, no. 9: 431. https://doi.org/10.3390/biom9090431

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