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.
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.
Soghomonian
Jean-Jacques
JJ
Department of Anatomy and Neurobiology, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA. jjsogho@bu.edu
D000818:Animals; D001345:Autoradiography / Q000379:methods; D001522:Behavior, Animal; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000009:adverse effects*; D018765:Dopamine Uptake Inhibitors / Q000493:pharmacokinetics; D020820:Dyskinesias / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D007839:Functional Laterality; D015870:Gene Expression / Q000187:drug effects; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D008454:Mazindol / Q000493:pharmacokinetics; D009474:Neurons / Q000187:drug effects*; D016627:Oxidopamine / Q000633:toxicity; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000293:injuries; D020531:Subthalamic Nucleus / Q000166:cytology* / Q000187:drug effects; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics
D015259:Dopamine Agents; D018765:Dopamine Uptake Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D014316:Tritium; D007980:Levodopa; D016627:Oxidopamine; D008454:Mazindol; D004298:Dopamine