L-DOPA-induced dyskinesia in adult rats with a unilateral 6-OHDA lesion of dopamine neurons is paralleled by increased c-fos gene expression in the subthalamic nucleus

• Published in: The European journal of neuroscience 2006-05, Vol.23 (9), p.2395-2403
• Main Author: Soghomonian, Jean-Jacques
• Format: Article
• Language: English
• Subjects: 6-hydroxydopamine; Animals; Autoradiography - methods; basal ganglia; Behavior, Animal; c-fos; Dopamine - metabolism; Dopamine Agents - adverse effects; Dopamine Uptake Inhibitors - pharmacokinetics; dyskinesia; Dyskinesias - etiology; Dyskinesias - metabolism; Dyskinesias - physiopathology; Functional Laterality; Gene Expression - drug effects; Immunohistochemistry - methods; In Situ Hybridization - methods; levodopa; Levodopa - adverse effects; Male; Mazindol - pharmacokinetics; Neurons - drug effects; Oxidopamine - toxicity; Parkinson's disease; Proto-Oncogene Proteins c-fos - genetics; Proto-Oncogene Proteins c-fos - metabolism; Rats; Rats, Sprague-Dawley; Substantia Nigra - injuries; Subthalamic Nucleus - cytology; Subthalamic Nucleus - drug effects; Time Factors; Tritium - pharmacokinetics
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/j.1460-9568.2006.04758.x

Levodopa (L‐DOPA), the metabolic precursor of dopamine, is widely used as a pharmacological agent for the symptomatic treatment of Parkinson's disease. However, long‐term L‐DOPA use results in abnormal involuntary movements such as dyskinesias. There is evidence that abnormal cell signaling in the basal ganglia is involved in L‐DOPA‐induced dyskinesia. The subthalamic nucleus (STN) plays a key role in the circuitry of the basal ganglia and in the pathophysiology of Parkinson's disease. However, the contribution of the STN to L‐DOPA‐induced dyskinesias remains unclear. The objective of this work was to study the effects of acute or chronic systemic administration of L‐DOPA to adult rats with a unilateral 6‐hydroxydopamine (6‐OHDA) lesion of dopamine neurons on c‐fos expression in the STN and test the hypothesis that these effects correlate with L‐DOPA‐induced dyskinesias. c‐fos mRNA expression was measured in the STN by in situ hybridization histochemistry at the single cell level. Our results confirm earlier evidence that the chronic administration of L‐DOPA to rats with a unilateral 6‐OHDA lesion increases c‐fos expression in the STN. We also report that c‐fos expression can be increased following an acute injection of L‐DOPA to 6‐OHDA‐lesioned rats but not following a chronic injection of L‐DOPA to sham‐operated, unlesioned rats. Finally, we provide evidence that the occurrence and severity of dyskinesia is correlated with c‐fos mRNA levels in the ipsilateral STN. These results suggest that altered cell signaling in the STN is involved in some of the behavioral effects induced by systemic L‐DOPA administration.