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The selective D(3) receptor antagonist, S33084, improves parkinsonian-like motor dysfunction but does not affect L-DOPA-induced dyskinesia in 6-hydroxydopamine hemi-lesioned rats.
Neuropharmacology. 2010 Feb; 58(2):528-36.N

Abstract

Despite evidence linking dopamine D(3) receptors to the etiology of Parkinson's disease and L-DOPA-induced dyskinesia, the potential therapeutic utility of D(3) receptor ligands remains unclear. In the present study, we investigated whether the selective D(3) receptor antagonist, S33084, affects development and expression of abnormal involuntary movements (AIMs), a behavioural correlate of dyskinesia, in rats hemi-lesioned with 6-hydroxydopamine and chronically treated with L-DOPA. The ability of S33084, alone or in combination with L-DOPA, to attenuate 6-hydroxydopamine induced motor deficits was also investigated employing a battery of behavioural tests. Acute administration of S33084 (0.64 mg/kg, s.c.) did not attenuate the induction of AIMs in dyskinetic rats upon challenge with L-DOPA (6 mg/kg, s.c.). Moreover, S33084 (0.64 mg/kg) did not prevent the development of AIMs affecting axial, limb and orolingual muscles when chronically administered together with L-DOPA (6 mg/kg for 21 days). However, both acute and chronic administration of S33084 enhanced L-DOPA-induced contralateral turning, suggesting potential antiparkinsonian properties. Furthermore, S33084 (0.01-0.64 mg/kg) dose-dependently attenuated parkinsonian disabilities, including bradykinesia, in drag and rotarod tests, although, in these procedures, the combination of S33084 with L-DOPA did not produce synergistic effect. It is concluded that sustained D(3) receptor blockade does not blunt L-DOPA-induced dyskinesia in hemiparkinsonian rats. However, D(3) receptor antagonism may be associated with antiparkinsonian properties. The clinical relevance of these observations will be of interest to explore further.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Mela F
Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, via Fossato di Mortara 17-19, 44100 Ferrara, Italy.
Millan MJ
No affiliation info available
Brocco M
No affiliation info available
Morari M
No affiliation info available

MeSH

AnimalsAntiparkinson AgentsBenzopyransDisability EvaluationDopamine AntagonistsDose-Response Relationship, DrugDrug InteractionsDyskinesia, Drug-InducedHypokinesiaLevodopaMaleOxidopamineParkinsonian DisordersPyrrolesRatsRats, Sprague-DawleyReceptors, Dopamine D3Time FactorsTreatment Outcome

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19733554

Citation

Mela, Flora, et al. "The Selective D(3) Receptor Antagonist, S33084, Improves Parkinsonian-like Motor Dysfunction but Does Not Affect L-DOPA-induced Dyskinesia in 6-hydroxydopamine Hemi-lesioned Rats." Neuropharmacology, vol. 58, no. 2, 2010, pp. 528-36.
Mela F, Millan MJ, Brocco M, et al. The selective D(3) receptor antagonist, S33084, improves parkinsonian-like motor dysfunction but does not affect L-DOPA-induced dyskinesia in 6-hydroxydopamine hemi-lesioned rats. Neuropharmacology. 2010;58(2):528-36.
Mela, F., Millan, M. J., Brocco, M., & Morari, M. (2010). The selective D(3) receptor antagonist, S33084, improves parkinsonian-like motor dysfunction but does not affect L-DOPA-induced dyskinesia in 6-hydroxydopamine hemi-lesioned rats. Neuropharmacology, 58(2), 528-36. https://doi.org/10.1016/j.neuropharm.2009.08.017
Mela F, et al. The Selective D(3) Receptor Antagonist, S33084, Improves Parkinsonian-like Motor Dysfunction but Does Not Affect L-DOPA-induced Dyskinesia in 6-hydroxydopamine Hemi-lesioned Rats. Neuropharmacology. 2010;58(2):528-36. PubMed PMID: 19733554.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The selective D(3) receptor antagonist, S33084, improves parkinsonian-like motor dysfunction but does not affect L-DOPA-induced dyskinesia in 6-hydroxydopamine hemi-lesioned rats. AU - Mela,Flora, AU - Millan,Mark J, AU - Brocco,Mauricette, AU - Morari,Michele, Y1 - 2009/09/04/ PY - 2009/05/04/received PY - 2009/07/10/revised PY - 2009/08/25/accepted PY - 2009/9/8/entrez PY - 2009/9/8/pubmed PY - 2010/4/14/medline SP - 528 EP - 36 JF - Neuropharmacology JO - Neuropharmacology VL - 58 IS - 2 N2 - Despite evidence linking dopamine D(3) receptors to the etiology of Parkinson's disease and L-DOPA-induced dyskinesia, the potential therapeutic utility of D(3) receptor ligands remains unclear. In the present study, we investigated whether the selective D(3) receptor antagonist, S33084, affects development and expression of abnormal involuntary movements (AIMs), a behavioural correlate of dyskinesia, in rats hemi-lesioned with 6-hydroxydopamine and chronically treated with L-DOPA. The ability of S33084, alone or in combination with L-DOPA, to attenuate 6-hydroxydopamine induced motor deficits was also investigated employing a battery of behavioural tests. Acute administration of S33084 (0.64 mg/kg, s.c.) did not attenuate the induction of AIMs in dyskinetic rats upon challenge with L-DOPA (6 mg/kg, s.c.). Moreover, S33084 (0.64 mg/kg) did not prevent the development of AIMs affecting axial, limb and orolingual muscles when chronically administered together with L-DOPA (6 mg/kg for 21 days). However, both acute and chronic administration of S33084 enhanced L-DOPA-induced contralateral turning, suggesting potential antiparkinsonian properties. Furthermore, S33084 (0.01-0.64 mg/kg) dose-dependently attenuated parkinsonian disabilities, including bradykinesia, in drag and rotarod tests, although, in these procedures, the combination of S33084 with L-DOPA did not produce synergistic effect. It is concluded that sustained D(3) receptor blockade does not blunt L-DOPA-induced dyskinesia in hemiparkinsonian rats. However, D(3) receptor antagonism may be associated with antiparkinsonian properties. The clinical relevance of these observations will be of interest to explore further. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/19733554/The_selective_D_3__receptor_antagonist_S33084_improves_parkinsonian_like_motor_dysfunction_but_does_not_affect_L_DOPA_induced_dyskinesia_in_6_hydroxydopamine_hemi_lesioned_rats_ DB - PRIME DP - Unbound Medicine ER -