Dual effects of intermittent or continuous L-DOPA administration on gene expression in the globus pallidus and subthalamic nucleus of adult rats with a unilateral 6-OHDA lesion.
Intermittent oral doses of levodopa (L-DOPA) are routinely used to treat Parkinson's disease, but with prolonged use can result in adverse motor complications, such as dyskinesia. Continuous administration of L-DOPA achieves therapeutic efficacy without producing this effect, yet the molecular mechanisms are unclear. This study examined, by in situ hybridization histochemistry, the effects of continuous or intermittent L-DOPA administration on gene expression in the globus pallidus and subthalamic nucleus of adult rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway. Results were compared to 6-OHDA-treated rats receiving vehicle. Our results provide original evidence that continuous L-DOPA normalizes the 6-OHDA-lesion-induced increase in mRNA levels encoding for the 67 kDa isoform of glutamate decarboxylase in neurons of the globus pallidus and cytochrome oxidase subunit I mRNA levels in the subthalamic nucleus. The extent of normalization did not differ between the continuous and intermittent groups. In addition, intermittent L-DOPA induced an increase in the mRNA levels encoding for the 65 kDa isoform of glutamate decarboxylase in globus pallidus neurons ipsilateral to the lesion and a bilateral increase in c-fos mRNA expression in the subthalamic nucleus. These results suggest that continuous L-DOPA tends to normalize the 6-OHDA-lesion-induced alterations in cell signaling in the pallido-subthalamic loop. On the other hand, we propose that chronic intermittent L-DOPA exerts a dual effect by normalizing cell signaling in a subpopulation of neurons in the globus pallidus and subthalamic nucleus while inducing abnormal signaling in another subpopulation.
Nielsen
Kirsten M
KM
Department of Anatomy and Neurobiology, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA.
Soghomonian
Jean-Jacques
JJ
D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005917:Globus Pallidus / Q000187:drug effects* / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000378:metabolism; D017403:In Situ Hybridization; D007527:Isoenzymes / Q000378:metabolism; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D008454:Mazindol / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D016627:Oxidopamine; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects; D020531:Subthalamic Nucleus / Q000187:drug effects* / Q000378:metabolism
D015259:Dopamine Agents; D018765:Dopamine Uptake Inhibitors; D007527:Isoenzymes; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D007980:Levodopa; D016627:Oxidopamine; D008454:Mazindol; D003576:Electron Transport Complex IV; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2; D004298:Dopamine