Bilateral subthalamic nucleus lesion reverses L-dopa-induced motor fluctuations and facilitates dyskinetic movements in hemiparkinsonian rats.
Glutamatergic overactivity might be involved in L-dopa-induced motor complications since glutamate antagonists reverse and prevent L-dopa-induced shortening in motor response duration in 6-hydroxydopamine-lesioned (6-OHDA) rats and improve L-dopa-induced dyskinesias in parkinsonian monkeys and in patients with Parkinson's disease (PD). An increase in the subthalamic nucleus (STN) glutamatergic activity is believed to contribute to the pathophysiology of PD. However, the role of STN activity in L-dopa-induced motor complications is not so clear. In this study, the effect of STN lesions on L-dopa-induced motor response complications was investigated in rats with a nigrostriatal pathway lesion induced by 6-OHDA. Animals were injected with 6-OHDA in the medial forebrain bundle and treated with L-dopa or saline for 22 days. On day 16, animals were randomly distributed in groups that underwent surgery in the STN ipsilateral or contralateral to 6-OHDA lesion, or bilateral. Rotational behavior was measured on days 1, 15, and 22. Attenuation of STN activity by contralateral and bilateral, but not ipsilateral, STN lesion reversed the shortening in motor response duration induced by L-dopa. L-dopa administration, but not saline, induced prominent dyskinesias in 6-OHDA-lesioned rats with additional bilateral STN lesions. The results indicate that bilateral lesions of STN potentiate the duration of L-dopa-induced motor response and facilitate chronic L-dopa-induced abnormal involuntary movements in 6-OHDA-lesioned rats. The characteristics of the abnormal involuntary movements observed in these animals are similar to L-dopa-induced dyskinesias in parkinsonian patients and might be useful as an experimental model for the study of L-dopa-induced dyskinesia.
Marin
Concepció
C
Laboratori de Neurologia Experimental, Fundació Clínic-Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain. cmarin@medicina.ub.es
Jiménez
Anna
A
Tolosa
Eduardo
E
Bonastre
Mercè
M
Bové
Jordi
J
D000818:Animals; D000978:Antiparkinson Agents / Q000633:toxicity*; D001522:Behavior, Animal; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020820:Dyskinesias / Q000209:etiology*; D007839:Functional Laterality; D007980:Levodopa / Q000037:antagonists & inhibitors / Q000633:toxicity*; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009068:Movement / Q000187:drug effects / Q000502:physiology; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012399:Rotation; D013239:Stereotyped Behavior / Q000187:drug effects*; D020531:Subthalamic Nucleus / Q000187:drug effects / Q000473:pathology*; D013997:Time Factors
D000978:Antiparkinson Agents; D007980:Levodopa; D016627:Oxidopamine