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

• Published in: Synapse (New York, N.Y.) N.Y.), 2003-09, Vol.49 (4), p.246-260
• Main Authors: Nielsen, Kirsten M., Soghomonian, Jean-Jacques
• Format: Article
• Language: English
• Subjects: 6-hydroxydopamine; Animals; Autoradiography; Behavior, Animal; behavioral sensitization; c-fos; cytochrome oxidase; Dopamine - metabolism; Dopamine Agents - pharmacology; Dopamine Uptake Inhibitors - metabolism; dyskinesia; Electron Transport Complex IV - metabolism; Gene Expression Regulation - drug effects; Gene Expression Regulation, Enzymologic - drug effects; Globus Pallidus - drug effects; Globus Pallidus - metabolism; glutamate decarboxylase; Glutamate Decarboxylase - metabolism; In Situ Hybridization; Isoenzymes - metabolism; levodopa; Levodopa - pharmacology; Male; Mazindol - metabolism; Neurons - drug effects; Oxidopamine; Parkinson's disease; Proto-Oncogene Proteins c-fos - metabolism; Rats; Rats, Sprague-Dawley; RNA, Messenger - metabolism; Substantia Nigra - drug effects; Subthalamic Nucleus - drug effects; Subthalamic Nucleus - metabolism
• ISSN: 0887-4476; 1098-2396
• DOI: 10.1002/syn.10234

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. Synapse 49:246–260, 2003. © 2003 Wiley‐Liss, Inc.