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Subthalamic 6-OHDA-induced lesion attenuates levodopa-induced dyskinesias in the rat model of Parkinson's disease.
Exp Neurol. 2013 Dec; 250:304-12.EN

Abstract

The subthalamic nucleus (STN) receives direct dopaminergic innervation from the substantia nigra pars compacta that degenerates in Parkinson's disease. The present study aimed to investigate the role of dopaminergic denervation of STN in the origin of levodopa-induced dyskinesias. Rats were distributed in four groups which were concomitantly lesioned with 6-OHDA or vehicle (sham) in the STN and in the medial forebrain bundle (MFB) as follows: a) MFB-sham plus STN-sham, b) MFB-sham plus STN-lesion, c) MFB-lesion plus STN-sham, and d) MFB-lesion plus STN-lesion. Four weeks after lesions, animals were treated with levodopa (6mg/kg with 15mg/kg benserazide i.p.) twice daily for 22 consecutive days. Abnormal involuntary movements were measured. In situ hybridization was performed measuring the expression of striatal preproenkephalin, preprodynorphin, STN cytochrome oxidase (CO) and nigral GAD67 mRNAs. STN 6-OHDA denervation did not induce dyskinesias in levodopa-treated MFB-sham animals but attenuated axial (p<0.05), limb (p<0.05) and orolingual (p<0.01) dyskinesias in rats with a concomitant lesion of the nigrostriatal pathway. The attenuation of dyskinesias was associated with a decrease in the ipsilateral STN CO mRNA levels (p<0.05). No significant differences between MFB-lesion plus STN-sham and MFB-lesion plus STN-lesion groups in the extent of STN dopaminergic denervation were observed. Moreover, intrasubthalamic microinfusion of dopamine in the MFB-lesion plus STN-lesion group triggered orolingual (p<0.01), but not axial or limb, dyskinesias. These results suggest that dopaminergic STN innervation influences the expression of levodopa-induced dyskinesias but also the existence of non dopaminergic-mediated mechanisms. STN noradrenergic depletion induced by 6-OHDA in the STN needs to be taken in account as a possible mechanism explaining the attenuation of dyskinesias in the combined lesion group.

Authors+Show Affiliations

INGENIO, IRCE, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS-CELLEX), Barcelona, Spain; Centro de Investigación en Redes sobre Enfermedades Neurodegenerativas (CIBERNED), Spain. Electronic address: cmarin@clinic.ub.es.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

24140562

Citation

Marin, C, et al. "Subthalamic 6-OHDA-induced Lesion Attenuates Levodopa-induced Dyskinesias in the Rat Model of Parkinson's Disease." Experimental Neurology, vol. 250, 2013, pp. 304-12.
Marin C, Bonastre M, Mengod G, et al. Subthalamic 6-OHDA-induced lesion attenuates levodopa-induced dyskinesias in the rat model of Parkinson's disease. Exp Neurol. 2013;250:304-12.
Marin, C., Bonastre, M., Mengod, G., Cortés, R., Rodríguez-Oroz, M. C., & Obeso, J. A. (2013). Subthalamic 6-OHDA-induced lesion attenuates levodopa-induced dyskinesias in the rat model of Parkinson's disease. Experimental Neurology, 250, 304-12. https://doi.org/10.1016/j.expneurol.2013.10.006
Marin C, et al. Subthalamic 6-OHDA-induced Lesion Attenuates Levodopa-induced Dyskinesias in the Rat Model of Parkinson's Disease. Exp Neurol. 2013;250:304-12. PubMed PMID: 24140562.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Subthalamic 6-OHDA-induced lesion attenuates levodopa-induced dyskinesias in the rat model of Parkinson's disease. AU - Marin,C, AU - Bonastre,M, AU - Mengod,G, AU - Cortés,R, AU - Rodríguez-Oroz,M C, AU - Obeso,J A, Y1 - 2013/10/18/ PY - 2013/08/10/received PY - 2013/09/27/revised PY - 2013/10/02/accepted PY - 2013/10/22/entrez PY - 2013/10/22/pubmed PY - 2014/1/31/medline KW - 6-Hydroxydopamine KW - Basal ganglia KW - Cytochrome oxidase KW - Dyskinesia KW - Parkinson's disease KW - Preprodynorphin KW - Preproenkephalin KW - Subthalamic nucleus SP - 304 EP - 12 JF - Experimental neurology JO - Exp Neurol VL - 250 N2 - The subthalamic nucleus (STN) receives direct dopaminergic innervation from the substantia nigra pars compacta that degenerates in Parkinson's disease. The present study aimed to investigate the role of dopaminergic denervation of STN in the origin of levodopa-induced dyskinesias. Rats were distributed in four groups which were concomitantly lesioned with 6-OHDA or vehicle (sham) in the STN and in the medial forebrain bundle (MFB) as follows: a) MFB-sham plus STN-sham, b) MFB-sham plus STN-lesion, c) MFB-lesion plus STN-sham, and d) MFB-lesion plus STN-lesion. Four weeks after lesions, animals were treated with levodopa (6mg/kg with 15mg/kg benserazide i.p.) twice daily for 22 consecutive days. Abnormal involuntary movements were measured. In situ hybridization was performed measuring the expression of striatal preproenkephalin, preprodynorphin, STN cytochrome oxidase (CO) and nigral GAD67 mRNAs. STN 6-OHDA denervation did not induce dyskinesias in levodopa-treated MFB-sham animals but attenuated axial (p<0.05), limb (p<0.05) and orolingual (p<0.01) dyskinesias in rats with a concomitant lesion of the nigrostriatal pathway. The attenuation of dyskinesias was associated with a decrease in the ipsilateral STN CO mRNA levels (p<0.05). No significant differences between MFB-lesion plus STN-sham and MFB-lesion plus STN-lesion groups in the extent of STN dopaminergic denervation were observed. Moreover, intrasubthalamic microinfusion of dopamine in the MFB-lesion plus STN-lesion group triggered orolingual (p<0.01), but not axial or limb, dyskinesias. These results suggest that dopaminergic STN innervation influences the expression of levodopa-induced dyskinesias but also the existence of non dopaminergic-mediated mechanisms. STN noradrenergic depletion induced by 6-OHDA in the STN needs to be taken in account as a possible mechanism explaining the attenuation of dyskinesias in the combined lesion group. SN - 1090-2430 UR - https://www.unboundmedicine.com/medline/citation/24140562/Subthalamic_6_OHDA_induced_lesion_attenuates_levodopa_induced_dyskinesias_in_the_rat_model_of_Parkinson's_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-4886(13)00309-9 DB - PRIME DP - Unbound Medicine ER -